The Cerebellum

https://doi.org/10.1007/s12311-023-01562-0

REVIEW

A Review of Brain and Pituitary Gland MRI Findings in Patients

with Ataxia and Hypogonadism
Alessandra Scaravilli1 · Mario Tranfa1 · Giuseppe Pontillo1,2 · Bernard Brais3 · Giovanna De Michele4 ·
Roberta La Piana3 · Francesco Saccà4 · Filippo Maria Santorelli5 · Matthis Synofzik6,7 · Arturo Brunetti1 ·
Sirio Cocozza1

Accepted: 26 April 2023

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023

Abstract
The association of cerebellar ataxia and hypogonadism occurs in a heterogeneous group of disorders, caused by different
genetic mutations often associated with a recessive inheritance. In these patients, magnetic resonance imaging (MRI) plays
a pivotal role in the diagnostic workflow, with a variable involvement of the cerebellar cortex, alone or in combination with
other brain structures. Neuroimaging involvement of the pituitary gland is also variable. Here, we provide an overview of
the main clinical and conventional brain and pituitary gland MRI imaging findings of the most common genetic mutations
associated with the clinical phenotype of ataxia and hypogonadism, with the aim of helping neuroradiologists in the iden-
tification of these disorders.

Keywords Ataxia · Hypogonadism · Conventional MRI · Pituitary gland

* Sirio Cocozza Arturo Brunetti

sirio.cocozza@unina.it brunetti@unina.it
Alessandra Scaravilli 1
Department of Advanced Biomedical Sciences, University
alessandra.scaravilli@gmail.com
of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy
Mario Tranfa 2
Department of Electrical Engineering and Information
mariotranfa@libero.it
Technology (DIETI), University of Naples “Federico II”,
Giuseppe Pontillo Naples, Italy
giuseppe.pon@gmail.com 3
Department of Neurology and Neurosurgery, Montreal
Bernard Brais Neurological Hospital and Institute, Montreal, Canada
Bernard.brais@mcgill.ca 4
Department of Neurosciences and Reproductive
Giovanna De Michele and Odontostomatological Sciences, University of Naples
giodemic@gmail.com “Federico II”, Naples, Italy
5
Roberta La Piana Department of Molecular Medicine, IRCCS Stella Maris
Roberta.lapiana@mcgill.ca Foundation, Pisa, Italy
6
Francesco Saccà German Center for Neurodegenerative Diseases (DZNE),
Francesco.sacca@unina.it Tubingen, Germany
7
Filippo Maria Santorelli Division Translational Genomics of Neurodegenerative
filippo3364@gmail.com Diseases, Center for Neurology and Hertie Institute
for Clinical Brain Research, University of Tübingen,
Matthis Synofzik
Otfried‑Müller‑Strasse 27, 72076 Tubingen, Germany
matthis.synofzik@uni-tuebingen.de

1 Vol.:(0123456789)
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Introduction
The occurrence of cerebellar ataxia in association with hypo-
gonadism has been described for the first time more than
100 years ago [1]. Although being a rare event, this combina-
tion is associated with a heterogeneous spectrum of genes/
loci, mostly autosomal recessively inherited [2]. Besides the
core features of cerebellar ataxia and hypogonadotropic hypo-
gonadism, most conditions present a wide range of symptoms,
encompassing cerebellar and extracerebellar symptoms, vari-
able degree of cognitive involvement, spasticity, epilepsy, and
oculomotor apraxia [2].
A similarly high level of heterogeneity is also pre-
sent on conventional magnetic resonance imaging (MRI)
scans, with changes ranging from cerebellar atrophy (a
constant feature, with a variable degree of involvement)
to cerebral atrophy, white matter (WM), and basal gan-
glia (BG) signal changes. Furthermore, hypogonadism is
a main clinical feature, but the pituitary gland does not
always show a typical corresponding alteration on imag-
ing. In this light, it is also noteworthy to mention that
although a univocal definition of reduced pituitary gland
volume is still lacking, a cut-off of 4 mm measured on
coronal T1-weighted images (WI) as has been previously
proposed to discriminate between a normal and a hypo-
plastic gland [3–6].
Although the level of heterogeneity is ample, consist-
ent MRI features seem to associate with specific genes
whose knowledge and prompt recognition can help the
neuroradiologist in their identification, providing impor-
tant information to guide clinicians in the differential diag-
nosis process and appropriate genetic testing.
In this review, we provide an overview of the conven-
tional brain and pituitary gland MRI findings in subjects
with the most common genetic mutations associated with
the clinical phenotype of ataxia and hypogonadism, with
Fig. 1  Brain MRI findings in a 44-year-old female RNF216 patient.
In A, a coronal multiplanar reconstruction of a T1-weighted
sequence showing the presence of diffuse cerebellar atrophy, cou-
pled to the presence of a global cortical atrophy (more conspicuous
13
The Cerebellum
the aim of helping neuroradiologists in the identification
of these disorders.
Conditions with high clinical, radiological, and genetic hetero-
geneity such as Perrault syndrome are excluded from this review.
RNF216
Mutations in the RNF216 gene are classically associated
with the Gordon Holmes syndrome (GHS) (MIM212840),
a rare neurodegenerative disorder defined by the presence
of hypogonadotropic hypogonadism, cerebellar ataxia, and
cognitive dysfunction, with digenic homozygous mutations
in RNF216 and OTUD4 [7, 8]. More recently, biallelic vari-
ants in RNF216 were described in association with clinical
features of chorea, behavioral disturbances, and progressive
dementia, configuring an autosomal recessive Huntington
disease-like phenotype (HDL) in the absence of the (CAG)n
expansion in the gene encoding huntingtin (HTT) [9].
On MRI, typical although nonspecific signs of the disease
are the presence of cortical atrophy, with a pronounced cer-
ebellar involvement [10], coupled to either focal or diffuse
T2 WI-hyperintensity affecting the periventricular, deep, and
subcortical WM (Fig. 1). Cerebellar WM usually appears
to be relatively spared [11]. A case of bilateral hyperinten-
sity of the dentate nuclei has been reported [12]. Bilateral
putaminal atrophy [13] and hyperintensity of the basal gan-
glia [7, 8, 10] have been also described, as well as a T2 WI-
hyperintensity of the brainstem [11, 13].
Pituitary gland usually show a preserved volume and sig-
nal [14] (Fig. 1).
STUB1
Mutations in the STUB1 gene (STIP1 homology and
U-box containing protein 1, E3 ubiquitin protein ligase),
which codes for the CHIP protein (C-terminus of
in the parietal regions) (B, T2-weighted axial image). In C, a coronal
T2-weighted image shows the presence of a preserved pituitary gland
(white arrow), along with scattered hyperintensity of the deep white
matter (arrowheads)
The Cerebellum
HSC70-interacting protein), have been associated with
both autosomal recessive (SCAR16) (MIM615768) and
dominant (SCA48) (MIM 618,093) forms of ataxia. The
spectrum of associated phenotypes is wide with a higher
prevalence in SCA48 patients of cognitive decline [15]
combined with behavioral changes and movement disor-
ders, such as chorea and Parkinsonism [16, 17]. On the
other hand, epilepsy seems to be more common in SCAR16
patients [18, 19]. Other phenotypes of mutations in STUB1
include atypical presentation of GHS, or variable presence
of hypogonadism [20], spasticity, epilepsy, and autonomic
dysfunction [15, 21].
This relative difference in clinical presentation is appar-
ently coupled to a similar heterogeneity in MRI appearance.
In particular, in line with the main clinical presentation of
both conditions, the common MRI feature is the presence
of marked cerebellar atrophy [19, 20, 22–24]. In SCA48,
the “crab sign” (defined as a more pronounced atrophy of
the posterior-lateral lobules of the cerebellum, with spar-
ing of the cerebellar peduncles and brainstem, coupled to a
T2 WI-hyperintensity of the dentate nuclei) has been pro-
posed as a neuroradiological feature of these patients (Fig. 2)
[25], while other STUB1 phenotypes seem to not share such
appearance on MRI, although a direct comparison is still
lacking. A mild supratentorial atrophy was also reported in
some STUB1 mutated cases [23, 25]. Additional brain MRI
findings described in STUB1-associated phenotypes are the
thinning of the anterior part of corpus callosum and in some
cases a slight atrophy of the brainstem [24]. Pituitary gland
is usually regular in volume and signal (Fig. 2), with only a
case of empty sella that has been reported in literature [24].
PNPLA6
Mutations in the PNPLA6 gene (Patatin-like phospholipase
domain-containing protein 6) are related to a continuum of
neurodegenerative disorders characterized by different clini-
cal features, such as ataxia, chorioretinal dystrophy, hypog-
onadotropic hypogonadism, and motor neuron disease [26,
Fig. 2  Axial T2- (A) and
T1-weighted (B) images
showing the presence of a
“crab sign” in a 59-year-old
female SCA48. In C, a sagittal
multiplanar reconstruction
of a T1-weighted sequence
shows the presence of a regular
pituitary gland appearance
(white arrow), in the context
of a persevered supratentorial
compartment
27], variably combined in four main clinical phenotype, all
associated with an autosomal recessive inheritance [28].
Imaging features of PNPLA6-associated mutations
include the presence of cerebellar atrophy [26, 27, 29, 30],
mostly vermian [31, 32], along with a variable pons [27] or
midbrain involvement [33] (Fig. 3). Brain signal changes
have also been reported, ranging from focal lesions [31] to
a diffuse and confluent T2 WI-hyperintensity of the perive-
ntricular WM, in the internal capsule and corona radiata
[34, 35].
A significant cord atrophy from T3 to T11 [36] has
been reported in the Spastic Paraplegia type 39 phenotype
(MIM612020) [37], while a mild medullar volume loss has
been described in the Oliver McFarlane syndrome [32].
Furthermore, a single anecdotal case of reduction of right
middle cerebral artery (MCA) branches was reported in a
Chinese patient with the Boucher-Neuhäuser Syndrome
(MIM215470) [29]. A small pituitary gland volume is com-
monly reported on MRI [27, 29, 34].
AARS2
Mutations of the mitochondrial Alanyl-tRNA synthetase
2 (AARS2) gene are associated with adult-onset pro-
gressive leukoencephalopathy with ovarian failure [38]
(MIM615889). Clinical presentation is nonspecific and often
similar to the one descripted in adult-onset leukoencepha-
lopathy with axonal spheroids and pigmented glia (ALSP)
[39, 40]. The onset is in the second/third decade of life with
prominent cognitive decline and psychiatric changes, associ-
ated with pyramidal and extrapyramidal signs, ataxia, sei-
zures, and ovarian failure [39].
This relative heterogeneity in clinical presentation is mir-
rored by a similar wide spectrum of MRI changes. Indeed,
cerebral and cerebellar atrophy are variably reported on MRI
[41, 42] (Fig. 4), with the latter showing a slightly apparent
predominant vermian involvement [38]. Usually reported in
this condition is the presence of large, asymmetric, conflu-
ent T2 WI-hyperintensity affecting the deep fronto-parietal
and periventricular WM (Fig. 4), associated with FLAIR
13

Fig. 3  Brain MRI findings in a 11-year-old male PNPLA6 patient.
Axial FLAIR image (A) shows regular parenchymal volume
and signal. Cerebellar hemispheres are also preserved in volume
(white arrowheads in B, a coronal multiplanar reconstruction of a
suppression due to WM rarefaction in the most severely
affected areas [38, 43]. Nevertheless, novel AARS2 muta-
tions were found in 2 patients without leukoencephalopathy
and cerebellar atrophy [44] and in 2 siblings with cerebellar
atrophy without leukoencephalopathy [45]. Other reported
features are the asymmetrical involvement of pyramidal
tracts and corpus callosum, and punctate or patchy areas
of restricted diffusion on DWI [43] (reported as “diffusion
dots” [40]). The corpus callosum abnormalities, that could
be limited to a single focal lesion or can affect a large part
of this structure with an inhomogeneous pattern [38], are
usually coupled to its thinning [43] (Fig. 4), which is nev-
ertheless less severe that the one found in ALSP patients
[40]. Finally, an inverted double lactate peak on both short
(30 ms) and long (135 ms) echo times on MRI spectroscopy
(MRS) in the altered WM has been reported in literature,
similarly to what reported in other mitochondrial encepha-
lopathies [42, 46].
Fig. 4  Brain MRI findings in a 40-year-old female AARS2 patient,
showing the presence of bilateral confluent fronto-parietal and perive-
ntricular white matter involvement (black arrowheads in A, an axial
FLAIR image). In B, a coronal T2-weighted image shows the pres-
13
The Cerebellum
T1-weighted sequence), while a vermian atrophy is present (black
arrowheads in B and C, with the latter being a sagittal T2-weighted
image). Pituitary gland is significantly reduced in volume (C, white
arrow)
No significant changes in volume or signal of the pituitary
gland have been to date reported in AARS2 patients [38,
40–42, 44–47] (Fig. 4).
SIL1
Mutations in the SIL1 gene, encoding for a resident endo-
plasmic reticulum glycoprotein, are associated with Mari-
nesco–Sjögren syndrome (MSS) (MIM248800), a rare
autosomal recessive infantile-onset multisystem disorder
characterized by the clinical triad of early-onset ataxia, bilat-
eral cataracts, and progressive myopathy, combined with var-
iable intellectual disability and delayed motor development
[48]. Additional frequent features are hypergonadotropic
hypogonadism, short stature, and skeletal abnormalities [49].
Most patients had elevated serum creatine kinase levels.
A marked cerebellar atrophy [48–50] is considered the
most consistent MRI finding in these patients (Fig. 5),
ence of a mild cerebral and cerebellar atrophy, without a peculiar pat-
tern of involvement, while in C (coronal T1-weighted sequence), the
presence of a callosal thinning (black arrows) with a normal pituitary
gland (with arrow) is shown
The Cerebellum

Fig. 5  Brain MRI findings in a

29-year-old female SIL1 patient.
Coronal FLAIR (A) and axial
T2-weighted (B) images show-
ing a marked cerebellar atrophy,
more pronounced in vermis,
with a mild hyperintensity of
the hemispheric cortex (A)

although some cases with absent or only minor vermian
atrophy have been reported [51]. Pontine atrophy is con-
sidered a rare finding [49]. A T2 WI-hyperintensity of the
cerebellar cortex, previously considered a neuroradiologi-
cal hallmark of infantile neuroaxonal dystrophy (INAD),
has also been anecdotally reported in three patients coupled
to a marked cerebellar atrophy [52], while some degree of
supratentorial WM changes has also been reported in this
condition [51]. With reference to pituitary appearance on
MRI, a reduced volume of the anterior portion of the gland
has been reported, along with the loss of the physiological
posterior pituitary “bright spot” (PPBS) on T1 WI [51, 53].
SETX
patients, early menopause [56], ovarian failure [57], and
polycystic ovarian syndrome [58] are also reported.
On MRI, a moderate to marked cerebellar atrophy is
reported in this condition, more severe in the vermis and
the anterior lobe [59–62] (Fig. 6). A recent imaging sign
suggested as typical of AOA patients is a reduction of the
normal hypointensity of dentate nuclei on SWI coupled to
a slight signal increase in T2 WI, which has been proposed
as a helpful neuroradiological sign to distinguish AOA from
other autosomal genetic cerebellar ataxias [63] (Fig. 6).
Brainstem atrophy, in association to cerebellar atrophy, has
been anecdotally reported [60]. No reports of altered pitui-
tary gland are available while studying large cohorts of AOA
patients [55, 56, 59, 61] (Fig. 6).

Mutations in the senataxin (SETX) gene, encoding a pos-

sible DNA/RNA helicase, are associated with ataxia with
oculomotor apraxia type 2 (AOA2) (MIM606002), a form
of autosomal recessive juvenile-onset progressive cerebellar
ataxia, characterized by sensorimotor peripheral neuropa-
thy, increased alpha-fetoprotein (AFP) serum levels, and
occasional oculomotor apraxia [54]. Other clinical features
reported in this condition are chorea, dystonia, strabismus,
and elevated creatine kinase serum levels [55]. In female
POLG
Mutations in the POLG gene, coding for the catalytic subu-
nit of mitochondrial DNA polymerase gamma, are the most
common single-gene cause of inherited mitochondrial disor-
ders [64] and the most frequent cause of mitochondrial epi-
lepsy [65]. POLG-related disorders comprise a continuum
of overlapping phenotypes (see [66] for a complete review),

Fig. 6  MRI findings in a

25-year-old female AOA2
patient. In A and B, coronal
and axial T2-weighted images
showing the presence of a mod-
erate diffuse cerebellar atrophy
and slight signal increase of the
dentate nuclei, respectively. A
preserved cerebral parenchyma
and pituitary gland appearance
can be observed in the sagittal
T1-weighted image (C)

13

the most severe being the Alpers–Huttenlocher syndrome
(AHS) (MIM203700), characterized by drug resistant epi-
lepsy, psychomotor delay, and hepatopathy in infants and
young children [67].
Abnormal MRI findings, more common in patients with
epilepsy [68], include cortical atrophy, either diffuse [68] or
with a more prominent parietal pattern [69, 70], along with
cerebellar atrophy [69, 71–73] (Fig. 7). WM changes are
also common and typical in subjects showing epilepsy, with
stroke-like lesions involving cortical and subcortical areas
[68], appearing as confluent hyperintense lesions on T2 WI
and FLAIR, typically involving the occipital lobe [72, 74,
75], and whose topography does not correspond to vascular
territories [69]. This pattern of significant WM involvement
is also present at the level of the infratentorial compartment,
affecting mainly the cerebellar WM [71, 76, 77] and the mid-
dle cerebellar peduncles (MCP) [78], while signal changes
at the level of midbrain and pons are less frequently reported
[79, 80]. Additional signal changes reported in these patients
are the presence of T2 WI-hyperintense lesions at the level
of the dorso-medial thalami [71, 81] and the basal ganglia
[68, 74, 82], as well as bilateral hypertrophic olivary hyper-
intensities, which should be differentiated from hypertrophic
olivary degeneration (HOD) [69, 70, 81, 83–86], especially
in phenotypes with progressive ataxia and palatal tremor
(PAPT) syndrome [70]. Atrophy or signal changes in DN
[83] have also been reported, often in patients with bilateral
lesions of the inferior olives [87, 88], while in AHS patients,
a severe cerebral atrophy and delayed myelination, along
with BG lesions, have also been described [89].
To date, no reports of significant changes in volume or
signal of the pituitary gland have been reported in POLG
patients [69, 70, 73, 79, 84, 90] (Fig. 7).
PMM2
Defects in the activity of phosphomannomutase 2 (associ-
ated with mutations in the PMM2 gene), an enzyme neces-
sary for the synthesis of GDP-mannose, represent the most
common cause of congenital disorder of N-glycosylation
(CDG) (MIM212065), a condition characterized by a broad
Fig. 7  MRI findings in a
35-year-old male POLG patient.
Sagittal T1-weighted image
(A) shows the presence of
mild cerebellar atrophy, with a
regular pituitary gland (white
arrow). A bilateral T2-weighted
hyperintensity at the level of
thalami (black arrowheads) and
cerebellar white matter (white
arrowheads) can be observed in
B and C, respectively
13
The Cerebellum
spectrum of clinical features ranging from severe neonatal
involvement to mild adulthood presentation as isolated neu-
rological syndrome or in association with ovarian failure
and hypogonadism [91]. Clinical findings include ataxia,
hypotonia, and abnormal eye movement, along with a pecu-
liar distribution of subcutaneous fat, inverted nipples, and
hypogonadism [92].
From a neuroimaging perspective, brain MRI can
be normal in infancy [93–97] and then presenting a
global, often progressive, cerebellar atrophy [98–105]
in the first decade of life, sometimes associated with
pons [106, 107], mid-pons, and clava atrophy [108] or
to severe olivo-pontocerebellar atrophy [109] (Fig. 8).
Some degree of cerebral atrophy [110], as well as T2
WI-hyperintensity affecting the WM [110], the cerebel-
lar cortex [111], and the dentate nuclei [109] have also
been reported (Fig. 8), while agenesis or hypoplasia of
the corpus callosum have been less often described [98,
112]. Some of these patients might undergo stroke-like
episodes, with variable imaging findings ranging from a
normal appearance [113, 114] to hemispheric vasogenic
subcortical/cortical oedema without restricted diffusion
[115–117] not corresponding to a specific vascular terri-
tory [118]. A global hyperintense appearance of cerebel-
lum (“bright cerebellum”) has been described in 5 Italian
patients [112].
An anecdotal case with a focal area of restricted diffusion
(cytotoxic oedema) due to occlusion of distal MCA and left
posterior cerebral artery (PCA), followed by cerebral atro-
phy, has also been reported [117].
With reference to pituitary gland imaging, to date, no
changes in volume or signal have been reported in PMM2
patients [98, 99, 103–109] (Fig. 8).
POLR3‑Related Leukodystrophies
Recessive mutations in the POLR3A (MIM607694),
POLR3B (MIM614381), and POLR1C (MIM610060) genes,
encoding the largest subunits of RNA polymerase III (Pol
III), have been reported to cause several allelic hypomyeli-
nating leukoencephalopathies, including hypomyelination
The Cerebellum
Fig. 8  Coronal (A) and axial (B) FLAIR images of a 33-year-old
male PMM2 patient showing the presence of a significant cerebellar
atrophy (with a mild dentate nuclei hyperintensity — white arrow-
with hypogonadotropic hypogonadism and hypodontia (4H
leukodystrophy) and leukodystrophy with oligodontia [119].
The common clinical findings in POLR3-associated muta-
tions are a variable degree of progressive upper motor neu-
ron dysfunction, ataxia, developmental delay, or intellectual
disability. On the other hand, the typical MRI pattern of
POLR3-related leukodystrophy is characterized by cerebel-
lar atrophy and thinning of the corpus callosum along with
diffuse T2 WI-hyperintensity of the cerebral WM, due to
hypomyelination, with preferential involvement of deep WM
and a relative sparing of U-fibers [120] (Fig. 9). A relative
T2 WI-hypointensity of the optic radiation, ventrolateral
thalamus, globus pallidus, corticospinal tract in the poste-
rior limb of the internal capsule (PLIC), and dentate nucleus
[121–124] are also common features on MRI (Fig. 9).
Although mutations in all genes present cerebellar atrophy
and hypomyelination as their principal MRI features, the
degree of hypomyelination is more severe in POLR3A muta-
tions, involving cerebral and cerebellar WM [119], while
POLR3B mutations present with milder hypomyelination
and clinical manifestation, but a marked cerebellar atrophy,
Fig. 9  Coronal (A), axial (B), and sagittal (C) T2-weighted images of
a 24-year-old POLR3A female patient showing the typical POLR3-
related leukodystrophy, with hyperintensity of the cerebral white
matter (black arrowheads), and a relative hypointensity of the globus
heads) in the context of a preserved cerebral parenchyma. In C, a sag-
ittal T2-weighted image confirming the presence of significant cer-
ebellar atrophy, with a normal pituitary gland (white arrow)
mostly in the vermis [119]. Furthermore, in atypical patterns
with predominant dystonia, atrophy and hyperintensity of
the striatum [125–127] and selective involvement of cor-
ticospinal tracts especially at the level of PLIC [128] were
reported. Less typical MRI finding is the presence of a T2
WI-hyperintensity along the superior cerebellar peduncles,
inferior cerebellar peduncles and peridentate WM [127,
129], and cervical cord atrophy [129].
Pituitary gland usually shows normal volumes on MRI
and no significant signal alterations, although in sev-
eral cases, an empty sella can be found in these patients
[119–123, 127–129] (Fig. 9).
WFS1
Wolfram syndrome-1 (MIM222300), caused by homozygous
or compound heterozygous mutation in the WFS1 gene, is
a rare and severe autosomal recessive neurodegenerative
disease. The acronym DIDMOAD, used synonymously,
describes the typical clinical features of this syndrome: dia-
betes insipidus (DI), diabetes mellitus (DM), optic atrophy
pallidus, ventrolateral thalamus, and optic radiation (black arrows),
along with thinning of the corpus callosum (white arrowheads). An
empty sella (white arrow) can be observed in C
13

Fig. 10  Brain MRI findings in a 51-year-old male WFS1 patient. In
A and B, axial FLAIR images showing respectively the presence of
a significant cerebellar atrophy, also involving the middle cerebellar
peduncles and the pons (stars in A and C), and the selective involve-
ment of bilateral optic radiations (black arrowheads in B). A magni-
fication of a sagittal T1-weighted sequence of the sellar region (C)
(OA), and deafness [130]. Additional clinical features
reported in patients with WFS1 mutations are renal abnor-
malities, neuropsychiatric disorders, and hypergonadotropic
hypogonadism [131]. On MRI, atrophy of cerebellum is an
almost constant finding in these patients, along with a vari-
able degree of MCP, brainstem and cerebral cortex volume
loss [130, 132–134] (Fig. 10), and a progressive atrophy of
the optic pathway [135]. Cases of a symmetrical periven-
tricular WM T2 WI-hyperintensity, limited to the area of
optic radiations, have been reported in literature [132, 136]
(Fig. 10), while in other reports, a diffuse leukoencephalopa-
thy pattern [136, 137] was found. More common seems to
be the presence of a T2 WI-hyperintensity and/or a T1 WI-
hypointensity of the ventral midline pons [133, 138–141].
Signal changes in substantia nigra (pars reticulata) [142]
were also anecdotally reported.
A typical feature of WFS1 patients is the loss of the physi-
ological T1 WI-hyperintensity of the posterior pituitary,
Fig. 11  Axial T2-weighted (A), FLAIR (B), and sagittal T1-weighted
(C) images of a 60-year-old male FXTAS patient showing the MCP
sign (black arrowheads in A) and the T2-hyperintensity of the sple-
nium of corpus callosum (black arrow in B), neuroradiological hall-
13
The Cerebellum
shows, along with chiasmatic atrophy as a further marker of optic
pathway involvement (black arrow), two additional major findings
in WFS1, namely, the loss of physiological T1 WI-hyperintensity of
the posterior pituitary (white arrow) and the thinning of infundibulum
and the hypothalamic region (white arrowheads)
along with the thinning of infundibulum and atrophy of the
hypothalamic region [132–134, 136, 138, 140, 142] (Fig. 10),
resulting in diabetes mellitus, due to hypothalamic degenera-
tion with neuronal loss and gliosis, as confirmed in histo-
pathological studies. In some cases, a normal posterior pitui-
tary bright spot can be found in patients with normal pituitary
hormones, showing only altered gonadotropins levels [131].
ATM
Mutations in the ATM gene, encoding a protein kinase
involved in DNA repair, are responsible for the develop-
ment of Ataxia-telangiectasia (AT) (MIM208900), the sec-
ond most common autosomal recessive ataxia [143]. The
onset of symptoms is usually in infancy or childhood, with
cerebellar ataxia, progressive oculocutaneous telangiecta-
sias, recurrent sinus and lung infections, and increased risk
of neoplasms [144]. Other clinical features found in subjects
marks of this condition. A moderate brain and cerebellar atrophy,
along with a T2 WI-hyperintensity of the deep and periventricular
WM, are also present, along with. A normal pituitary gland can be
observed in C (white arrow)
 Table 1  MRI findings of the most common mutations associated with ataxia and hypogonadism, without MRI changes of the pituitary gland
The Cerebellum

Atrophy WM signal changes Other significant MRI Pituitary gland

changes
Supratentorial Cerebellar Other Supratentorial Cerebellar Other

RNF216 Common, diffuse Common, marked Usually absent Common, extensive Usually absent Not common, brainstem T2w-hyperintensity of Usually normal
and mostly confluent, involvement the BG
bilateral subcortical
and periventricular T2
WI-hyperintensity
STUB1 Variable, absent to mild, Common, marked, Not common, thinning Usually absent Usually absent Usually absent In SCA48, DN Usually normal
without a specific mostly posterior and of anterior portion T2-weighted hyperin-
pattern inferior in SCA48 of CC (in recessive tensity (“crab sign”)
patients)
AARS2 Variable, usually mild Variable, mostly vermian Usually absent Common, exten- Usually absent Variable, involvement Usually absent Usually normal
sive, asymmetric, of CC and “diffusion
bilateral, and mostly dots” of restricted
fronto-parietal and diffusion
periventricular T2 WI-
hyperintensity
Not common: signs of
rarefaction
SETX Usually absent Common, moderate to Usually absent Usually absent Usually absent Usually absent Variable, absence of DN Usually normal
marked, mostly ante- hypointensity on SWI
rior lobe and vermis
POLG Common, mostly pari- Common, mild Common: presence of Common, with bilateral Variable, bilateral WM Not common, brainstem Not common, thalamic Usually normal
etal or diffuse HOD “stroke-like” lesions and MCP and BG lesions
Variable: DN atrophy in the subcortical WM
(typically occipital
lobe)
PMM2 Not common, diffuse Common, diffuse Common, olivopon- Variable, with bilateral Usually absent Usually absent Usually absent Usually normal
tocerebellar “stroke-like” lesions
ATM Usually absent Common, moderate, Usually absent Common, diffuse WM Usually absent Usually absent Common, hemosiderin Usually normal
mostly vermian involvement deposits and deep
cerebral telangiectatic
vessels
FXTAS Not common, moderate Variable, moderate Variable, brainstem Common, T2 WI- Common, “MCP sign” Variable, pons Usually absent Usually normal
hyperintensity of the
splenium of the CC;
variable, juxtacortical
and periventricular
WM

WM white matter, CC corpus callosum, BG basal ganglia, DN dentate nuclei, MCP middle cerebellar peduncle, HOD hypertrophic olivary degeneration, GP globus pallidus

13
13
Table 2  MRI findings of the most common mutations associated with ataxia and hypogonadism, with MRI changes of the pituitary gland
Atrophy WM signal changes Other significant Pituitary gland
MRI changes
Supratentorial Cerebellar Other Supratentorial Cerebellar Other

PNPLA6 Usually absent Common, marked Usually absent Not common, rang- Usually absent Usually absent Usually absent Small pituitary vol-
and mostly vermian ing from punctuate ume, with normal
to diffuse T2 WI- signal
hyperintensity
SIL1 Usually absent Variable, if present Usually absent Usually absent Usually absent Usually absent Not common, T2 Small anterior
marked and mostly WI-hyperintensity pituitary volume and
vermian of cerebellar cortex absence of PPBS
POLR3 Variable, diffuse Common, marked Common: thinning of Common, diffuse Variable, T2 WI- Variable, relative T2 Usually absent Empty sella
and mostly vermian the CC hypomyelination, hyperintensity WI-hypointensity
Variable: BG with relative T2 of SCP, ICP and of GP and DN
WI-hypointensity peridentate area
of the optic radia-
tion, WM adjacent
the ventrolateral
thalamus and
pyramidal tracts
WFS1 Variable, diffuse Common, marked Common: optic Variable: T2 WI- Usually absent Variable, T1 WI- Common, thinning Absence of PPBS with
and diffuse atrophy; Variable: hyperintensity of hypointensity/T2 of hypothalamus normal pituitary
MCP and brainstem the optic radiations WI-hyperintensity and infundibulum volume
Not common: diffuse of the pons
T2 WI-hyperin-
tensity

WM white matter, CC corpus callosum, BG basal ganglia, DN dentate nuclei, PPBS posterior pituitary bright spot, SCP superior cerebellar peduncle, MCP middle cerebellar peduncle, ICP infe-
rior cerebellar peduncle, GP globus pallidus
The Cerebellum
The Cerebellum
with AT are dysarthric speech, choreoathetosis, and ataxia
with oculomotor apraxia, with endocrine abnormalities such
as hypogonadism and elevated level of AFP in the CSF that
are also usually typically present in these patients [143].
Brain MRI might be normal in the first years of life. After
symptoms’ onset, abnormalities appear limited to the cere-
bellum [145] with a progressive cerebellar atrophy, predomi-
nantly vermian with less marked hemispheric involvement.
In young adults, imaging findings might include ischemic-
hemorrhagic complications and WM involvement [146] in
the form of diffuse T2 WI-hyperintensities [144, 147] often
surrounding punctate hypointense foci on SWI, represent-
ing hemosiderin deposits and/or telangiectasias [148]. Some
degree of spinal atrophy and signal changes in BG have also
been reported in older patients [149].
Pituitary gland is usually spared without reported signifi-
cant volumetric or signal changes [143–146, 150].
FXTAS
Fragile X-associated tremor/ataxia syndrome (FXTAS)
(MIM300623) is a progressive neurodegenerative movement
disorder characterized by balance problems, progressive
action tremor, and cognitive decline [151]. This phenotype
is associated with a premutation in the promoter region of
the Fragile X Mental Retardation 1 (FMR1) gene, defined
by 55–200 CGG repeats in the 5′-untranslated region, while
a larger CGG expansion (> 200) leads to the full mutation,
with the development of FXS [152]. The classic FXTAS
phenotype is represented by intentional tremor and gait
ataxia, and variable presence of peripheral neuropathy,
autonomic dysfunction, progressive cognitive decline, and
psychiatric disturbances [153, 154].
On MRI, the MCP sign (defined as the presence of bilateral
WM lesions in MCP) is a hallmark of this condition, along with
the T2 WI-hyperintensity of the splenium of corpus callosum,
with these sign that have been included in the revised diagnos-
tic criteria of the disease [155] (Fig. 11). Nevertheless, it has
to be remembered that the MCP sign occurs in about 60% of
affected males and in only 13% of affected females [156] and
is not a specific sign for FXTAS due to its presence in other
conditions such as the cerebellar subtype of multiple system
atrophy (MSA-C) or the acquired hepato-cerebral degeneration
[157]. On the other hand, lesions of the splenium of corpus cal-
losum are considered more reliable MRI signs of this condition
[158]. Additional MRI findings found in FXTAS patients are
moderate to severe generalized brain, brainstem, and cerebel-
lar atrophy, as well as a T2 WI-hyperintensity of the deep and
periventricular WM, DN, and pons [159, 160] (Fig. 11).
This heterogeneity in brain parenchymal findings in
FXTAS patients is not followed by a similar pattern of
changes of the pituitary gland, which is reported regular in
volume and signal [157, 158].
Conclusions
In this work, we have illustrated the neuroradiological find-
ings of the most common mutations associated with the
development of ataxia and hypogonadism. Main MRI char-
acteristics are summarized in two different tables (Tables 1
and 2), reflecting that some of these conditions are usually
characterized by a normal appearance of the pituitary gland,
while others show almost consistently changes detectable
with conventional MRI sequences. The role of neuroimaging
is crucial in these patients, and although these conditions
rarely show specific or pathognomonic MRI findings (and
therefore a “pure” neuroradiological differential diagnosis
might not be always possible), a careful combined evaluation
of MRI, together with the most important clinical features,
might guide the clinician in the direction of an appropriate
genetic testing, finally leading to the correct diagnosis.
Author Contribution All authors contributed to the study conception
and design. All authors read and approved the final manuscript. Ales-
sandra Scaravilli: conceptualization; writing — original draft prepara-
tion; Mario Tranfa: writing — review and editing; Giuseppe Pontillo:
writing — review and editing; Bernard Brais: writing — review and
editing; Giovanna De Michele: writing — review and editing; Rob-
erta La Piana: writing — review and editing; Francesco Saccà: writ-
ing — review and editing; Filippo Maria Santorelli: writing—review
and editing; Matthis Synofzik: writing — review and editing; Arturo
Brunetti: writing — review and editing; supervision; Sirio Cocozza:
conceptualization; writing — review and editing; supervision.
Data Availability Not applicable.
Declarations
Ethics Approval This report is a literature review and does not require
approval by an ethical committee.
Competing Interests The authors declare no competing interests.
References
1. Holmes G. A form of familial degeneration of the cerebellum.
Brain. 1908;30(4):466–89. https://​doi.​org/​10.​1093/​brain/​30.4.​466.
2. González-Latapi P, Sousa M, Lang A (2021) Movement disorders
associated with hypogonadism. Movement Disorders Clinical
Practice 8. https://​doi.​org/​10.​1002/​mdc3.​13308
3. Acharya SV, Gopal RA, Lila A, Sanghvi DS, Menon PS, Bandgar
TR, Shah NS. Phenotype and radiological correlation in patients
with growth hormone deficiency. Indian J Pediatr. 2011;78(1):49–
54. https://​doi.​org/​10.​1007/​s12098-​010-​0211-1.
4. Argyropoulou M, Perignon F, Brunelle F, Brauner R, Rappaport
R. Height of normal pituitary gland as a function of age evalu-
ated by magnetic resonance imaging in children. Pediatr Radiol.
1991;21(4):247–9. https://​doi.​org/​10.​1007/​BF020​18614.
5. Bortolotto Felippe Trentin M, Borges Daniel K, Reis F, Ado-
lfo Silva Junior N, Appenzeller S, Rittner L, Benetti Pinto C,
13

Garmes HM. Reconsidering the olfactory and brain structures
in Kallmann's syndrome: New findings in the analysis of volu-
metry. Clin Endocrinol (Oxf). 2023;98(4):554–8. https://d​ oi.o​ rg/​
10.​1111/​cen.​14868.
6. Zhang Z, Sun X, Wang C, Wang G, Zhao B. Magnetic Resonance
Imaging Findings in Kallmann Syndrome: 14 Cases and Review
of the Literature. J Comput Assist Tomogr. 2016;40(1):39–42.
https://​doi.​org/​10.​1097/​RCT.​00000​00000​000334.
7. Mehmood S, Hoggard N, Hadjivassiliou M. Gordon Hol-
mes syndrome: finally genotype meets phenotype. Pract
Neurol. 2017;17(6):476–8. https:// ​ d oi. ​ o rg/ ​ 1 0. ​ 1 136/ ​ p ract​
neurol-​2017-​001674.
8. Margolin DH, Kousi M, Chan YM, Lim ET, Schmahmann JD,
Hadjivassiliou M, Hall JE, Adam I, Dwyer A, Plummer L, Aldrin
SV, O'Rourke J, Kirby A, Lage K, Milunsky A, Milunsky JM,
Chan J, Hedley-Whyte ET, Daly MJ, Katsanis N, Seminara SB.
Ataxia, dementia, and hypogonadotropism caused by disordered
ubiquitination. N Engl J Med. 2013;368(21):1992–2003. https://​
doi.​org/​10.​1056/​NEJMo​a1215​993.
9. Wild EJ, Tabrizi SJ. Huntington's disease phenocopy syndromes.
Curr Opin Neurol. 2007;20(6):681–7. https://​doi.​org/​10.​1097/​
WCO.​0b013​e3282​f12074.
10. Calandra CR, Mocarbel Y, Vishnopolska SA, Toneguzzo V,
Oliveri J, Cazado EC, Biagioli G, Turjanksi AG, Marti M. Gor-
don Holmes Syndrome Caused by RNF216 Novel Mutation in 2
Argentinean Siblings. Mov Disord Clin Pract. 2019;6(3):259–62.
https://​doi.​org/​10.​1002/​mdc3.​12721.
11. Chen KL, Zhao GX, Wang H, Wei L, Huang YY, Chen SD, Lin
BY, Dong Q, Cui M, Yu JT. A novel de novo RNF216 mutation
associated with autosomal recessive Huntington‐like disorder. Ann
Clin Transl Neurol. 2020;7. https://​doi.​org/​10.​1002/​acn3.​51047
12. Lieto M, Galatolo D, Roca A, Cocozza S, Pontillo G, Fico T,
Pane C, Saccà F, De Michele G, Santorelli FM, Filla A. Overt
Hypogonadism May Not Be a Sentinel Sign of RING Finger Pro-
tein 216: Two Novel Mutations Associated with Ataxia, Chorea,
and Fertility. Mov Disord Clin Pract. 2019;6(8):724–6. https://​
doi.​org/​10.​1002/​mdc3.​12839.
13. Santens P, Van Damme T, Steyaert W, Willaert A, Sablonnière
B, De Paepe A, Coucke PJ, Dermaut B. RNF216 mutations as
a novel cause of autosomal recessive Huntington-like disorder.
Neurology. 2015;84(17):1760–6. https://​doi.​org/​10.​1212/​WNL.​
00000​00000​001521.
14. Alqwaifly M, Bohlega S. Ataxia and Hypogonadotropic hypog-
onadism with intrafamilial variability caused by RNF216 muta-
tion. Neurol Int. 2016;8(2):6444. https://d​ oi.o​ rg/1​ 0.4​ 081/n​ i.2​ 016.​
6444.
15. Mol MO, van Rooij JGJ, Brusse E, Verkerk AJMH, Melhem S,
den Dunnen WFA, Rizzu P, Cupidi C, van Swieten JC, Donker
Kaat L. Clinical and pathologic phenotype of a large family with
heterozygous STUB1 mutation. Neurol Genet. 2020;6(3):e417.
https://​doi.​org/​10.​1212/​NXG.​00000​00000​000417.
16. Palvadeau R, Kaya-Güleç ZE, Şimşir G, Vural A, Öztop-Çakmak
Ö, Genç G, Aygün MS, Falay O, Başak AN, Ertan S. Cerebel-
lar cognitive-affective syndrome preceding ataxia associated
with complex extrapyramidal features in a Turkish SCA48 fam-
ily. Neurogenetics. 2020;21(1):51–8. https://​doi.​org/​10.​1007/​
s10048-​019-​00595-0.
17. De Michele G, Lieto M, Galatolo D, Salvatore E, Cocozza S,
Barghigiani M, Tessa A, Baldacci J, Pappatà S, Filla A, De
Michele G, Santorelli FM. Spinocerebellar ataxia 48 presenting
with ataxia associated with cognitive, psychiatric, and extrapy-
ramidal features: a report of two Italian families. Parkinsonism
Relat Disord. 2019;65:91–6. https://d​ oi.o​ rg/1​ 0.1​ 016/j.p​ arkre​ ldis.​
2019.​05.​001.
18. De Michele G, Galatolo D, Barghigiani M, Dello Iacovo D, Tro-
vato R, Tessa A, Salvatore E, Filla A, De Michele G, Santorelli
13
The Cerebellum
FM. Spinocerebellar ataxia type 48: last but not least. Neu-
rol Sci. 2020 Sep;41(9):2423–32. https://​d oi.​o rg/​1 0.​1 007/​
s10072-​020-​04408-3.
19. Ravel J-M, Benkirane M, Calmels N, Marelli C, Ory-Magne F,
Ewenczyk C, Halleb Y, Tison F, Lecocq C, Pische G, Casenave
P, Chaussenot A, Frismand S, Tyvaert L, Larrieu L, Pointaux
M, Drouot N, Bossenmeyer-Pourié C, Oussalah A, Guéant J-L,
Leheup B, Bonnet C, Anheim M, Tranchant C, Lambert L,
Chelly J, Koenig M, Renaud M. Expanding the clinical spectrum
of STIP1 homology and U-box containing protein 1-associated
ataxia. J Neurol. 2021;268(5):1927–37. https://​doi.​org/​10.​1007/​
s00415-​020-​10348-x.
20. Shi CH, Schisler JC, Rubel CE, Tan S, Song B, McDonough
H, Xu L, Portbury AL, Mao CY, True C, Wang RH, Wang QZ,
Sun SL, Seminara SB, Patterson C, Xu YM. Ataxia and hypog-
onadism caused by the loss of ubiquitin ligase activity of the U
box protein CHIP. Hum Mol Genet. 2014;23(4):1013–24. https://​
doi.​org/​10.​1093/​hmg/​ddt497.
21. Hayer SN, Deconinck T, Bender B, Smets K, Züchner S, Reich S,
Schöls L, Schüle R, De Jonghe P, Baets J, Synofzik M. STUB1/
CHIP mutations cause Gordon Holmes syndrome as part of a
widespread multisystemic neurodegeneration: evidence from four
novel mutations. Orphanet J Rare Dis. 2017;12(1):31. https://d​ oi.​
org/​10.​1186/​s13023-​017-​0580-x.
22. Chiu H-H, Hsaio C-T, Tsai Y-S, Liao Y-C, Lee Y-C, Soong
B-W. Clinical and genetic characterization of autosomal reces-
sive spinocerebellar ataxia type 16 (SCAR16) in Taiwan.
The Cerebellum. 2020;19(4):544–9. https://​doi.​org/​10.​1007/​
s12311-​020-​01136-4.
23. Synofzik M, Schüle R, Schulze M, Gburek-Augustat J, Sch-
weizer R, Schirmacher A, Krägeloh-Mann I, Gonzalez M, Young
P, Züchner S, Schöls L, Bauer P. Phenotype and frequency of
STUB1 mutations: next-generation screenings in Caucasian
ataxia and spastic paraplegia cohorts. Orphanet J Rare Dis.
2014;9(1):57. https://​doi.​org/​10.​1186/​1750-​1172-9-​57.
24. Heimdal K, Sanchez-Guixé M, Aukrust I, Bollerslev J, Bruland
O, Jablonski GE, Erichsen AK, Gude E, Koht JA, Erdal S, Fisk-
erstrand T, Haukanes BI, Boman H, Bjørkhaug L, Tallaksen
CME, Knappskog PM, Johansson S. STUB1 mutations in auto-
somal recessive ataxias — evidence for mutation-specific clinical
heterogeneity. Orphanet J Rare Dis. 2014;9(1):146. https://​doi.​
org/​10.​1186/​s13023-​014-​0146-0.
25. Cocozza S, Pontillo G, De Michele G, Perillo T, Guerriero E,
Ugga L, Salvatore E, Galatolo D, Riso V, Saccà F, Quarantelli M,
Brunetti A. The "crab sign": an imaging feature of spinocerebel-
lar ataxia type 48. Neuroradiology. 2020;62(9):1095–103. https://​
doi.​org/​10.​1007/​s00234-​020-​02427-7.
26. Synofzik M, Kernstock C, Haack TB, Schöls L. Ataxia meets cho-
rioretinal dystrophy and hypogonadism: Boucher-Neuhäuser syn-
drome due to PNPLA6 mutations. J Neurol Neurosurg Psychiatry.
2015;86(5):580–1. https://​doi.​org/​10.​1136/​jnnp-​2014-​307793.
27. Synofzik M, Gonzalez MA, Lourenco CM, Coutelier M, Haack
TB, Rebelo A, Hannequin D, Strom TM, Prokisch H, Kernstock
C, Durr A, Schöls L, Lima-Martínez MM, Farooq A, Schüle R,
Stevanin G, Marques W Jr, Züchner S. PNPLA6 mutations cause
Boucher-Neuhauser and Gordon Holmes syndromes as part of a
broad neurodegenerative spectrum. Brain. 2014;137(Pt 1):69–77.
https://​doi.​org/​10.​1093/​brain/​awt326.
28. Melentev P, Agranovich O, Sarantseva S. Human diseases asso-
ciated with NTE gene. Ecol Genet. 2020;18. https://​doi.​org/​10.​
17816/​ecoge​n16327.
29. Zheng R, Zhao Y, Wu J, Wang Y, Liu JL, Zhou ZL, Zhou
XT, Chen DN, Liao WH, Li JD. A novel PNPLA6 compound
heterozygous mutation identified in a Chinese patient with
Boucher‑Neuhäuser syndrome. Mol Med Rep. 2018;18(1):261–
7. https://​doi.​org/​10.​3892/​mmr.​2018.​8955.
The Cerebellum
30. Yoon G, Baskin B, Tarnopolsky M, Boycott KM, Geraghty
MT, Sell E, Goobie S, Meschino W, Banwell B, Ray PN. Auto-
somal recessive hereditary spastic paraplegia—clinical and
genetic characteristics of a well-defined cohort. Neurogenetics.
2013;14(3):181–8. https://​doi.​org/​10.​1007/​s10048-​013-​0366-9.
31. Locci S, Bianchi S, Tessa A, Santorelli FM, Mignarri A. Gor-
don Holmes syndrome caused by two novel mutations in the
PNPLA6 gene. Clin Neurol Neurosurg. 2021;207:106763.
https://​doi.​org/​10.​1016/j.​cline​uro.​2021.​106763.
32. Patsi O, De Beaufort C, Kerschen P, Cardillo S, Soehn A, Rau-
tenberg M, Diederich NJ. A new PNPLA6 mutation presenting
as Oliver McFarlane syndrome. J Neurol Sci. 2018;392:1–2.
https://​doi.​org/​10.​1016/j.​jns.​2018.​06.​016.
33. Wiethoff S, Bettencourt C, Paudel R, Madon P, Liu Y-T,
Hersheson J, Wadia N, Desai J, Houlden H. Pure cerebel-
lar ataxia with homozygous mutations in the PNPLA6 gene.
The Cerebellum. 2017;16(1):262–7. https://​doi.​org/​10.​1007/​
s12311-​016-​0769-x.
34. Hufnagel RB, Arno G, Hein ND, Hersheson J, Prasad M,
Anderson Y, Krueger LA, Gregory LC, Stoetzel C, Jaworek
TJ, Hull S, Li A, Plagnol V, Willen CM, Morgan TM, Prows
CA, Hegde RS, Riazuddin S, Grabowski GA, Richardson RJ,
Dieterich K, Huang T, Revesz T, Martinez-Barbera JP, Sisk
RA, Jefferies C, Houlden H, Dattani MT, Fink JK, Dollfus H,
Moore AT, Ahmed ZM. Neuropathy target esterase impair-
ments cause Oliver-McFarlane and Laurence-Moon syn-
dromes. J Med Genet. 2015;52(2):85–94. https://​doi.​org/​10.​
1136/​jmedg​enet-​2014-​102856.
35. Kate M, Kesavadas C, Nair M, Krishnan S, Soman M, Singh
A. Late-onset Boucher-Neuhauser Syndrome (late BNS) associ-
ated with white-matter changes: a report of two cases and review
of literature. J Neurol Neurosurg Psychiatry. 2011;82:888–91.
https://​doi.​org/​10.​1136/​jnnp.​2009.​196790.
36. Rainier S, Albers J, Dyck P, Eldevik O, Wilcock S, Richard-
son R, Fink J. Motor neuron disease due to neuropathy target
esterase gene mutation: clinical features of the index families.
Muscle Nerve. 2011;43:19–25. https://​doi.​org/​10.​1002/​mus.​
21777.
37. Rainier S, Bui M, Mark E, Thomas D, Tokarz D, Ming L,
Delaney C, Richardson RJ, Albers JW, Matsunami N, Stevens
J, Coon H, Leppert M, Fink JK. Neuropathy target esterase
gene mutations cause motor neuron disease. Am J Hum Genet.
2008;82(3):780–5. https://​doi.​org/​10.​1016/j.​ajhg.​2007.​12.​018.
38. Dallabona C, Diodato D, Kevelam SH, Haack TB, Wong LJ,
Salomons GS, Baruffini E, Melchionda L, Mariotti C, Strom TM,
Meitinger T, Prokisch H, Chapman K, Colley A, Rocha H, Ounap
K, Schiffmann R, Salsano E, Savoiardo M, Hamilton EM, Abbink
TE, Wolf NI, Ferrero I, Lamperti C, Zeviani M, Vanderver A,
Ghezzi D, van der Knaap MS. Novel (ovario) leukodystrophy
related to AARS2 mutations. Neurology. 2014;82(23):2063–71.
https://​doi.​org/​10.​1212/​WNL.​00000​00000​000497.
39. Axelsen TM, Vammen TL, Bak M, Pourhadi N, Stenør CM,
Grønborg S. Case report: 'AARS2 leukodystrophy'. Mol Genet
Metab Rep. 2021;28:100782. https://​doi.​org/​10.​1016/j.​ymgmr.​
2021.​100782.
40. Lakshmanan R, Adams ME, Lynch DS, Kinsella JA, Phadke
R, Schott JM, Murphy E, Rohrer JD, Chataway J, Houlden H,
Fox NC, Davagnanam I. Redefining the phenotype of ALSP
and AARS2 mutation-related leukodystrophy. Neurol Genet.
2017;3(2):e135. https://​d oi.​o rg/​1 0.​1 212/​N XG.​0 0000​0 0000​
000135.
41. Srivastava S, Butala A, Mahida S, Richter J, Mu W, Poretti
A, Vernon H, VanGerpen J, Atwal PS, Middlebrooks EH,
Zee DS, Naidu S. Expansion of the clinical spectrum associ-
ated with AARS2-related disorders. Am J Med Genet A.
2019;179(8):1556–14. https://​doi.​org/​10.​1002/​ajmg.a.​61188.
42. Wang X, Wang Q, Tang H, Chen B, Dong X, Niu S, Li S,
Shi Y, Shan W, Zhang Z. Novel Alanyl-tRNA Synthetase
2 Pathogenic Variants in Leukodystrophies. Front Neurol.
2019;10:1321. https://​doi.​org/​10.​3389/​fneur.​2019.​01321.
43. Lynch DS, Zhang WJ, Lakshmanan R, Kinsella JA, Uzun GA,
Karbay M, Tüfekçioglu Z, Hanagasi H, Burke G, Foulds N,
Hammans SR, Bhattacharjee A, Wilson H, Adams M, Walker
M, Nicoll JA, Chataway J, Fox N, Davagnanam I, Phadke R,
Houlden H. Analysis of Mutations in AARS2 in a Series of
CSF1R-Negative Patients With Adult-Onset Leukoencepha-
lopathy With Axonal Spheroids and Pigmented Glia. JAMA
Neurol. 2016;73(12):1433–39. https://​doi.​org/​10.​1001/​jaman​
eurol.​2016.​2229.
44. De Michele G, Galatolo D, Lieto M, Maione L, Cocozza S,
Santorelli FM, Filla A. New AARS2 mutations in two siblings
with tremor, downbeat nystagmus, and primary amenorrhea: a
benign phenotype without leukoencephalopathy. Mov Disord
Clin Pract. 2020;7(6):684–7. https://​doi.​org/​10.​1002/​mdc3.​
12991.
45. Kuo ME, Antonellis A, Shakkottai VG. Alanyl-tRNA Syn-
thetase 2 (AARS2)-Related Ataxia Without Leukoencephalopa-
thy. Cerebellum. 2020;19(1):154-160. https://​doi.​org/​10.​1007/​
s12311-​019-​01080-y.
46. Taglia I, Di Donato I, Bianchi S, Cerase A, Monti L, Marconi R,
Orrico A, Rufa A, Federico A, Dotti MT. AARS2-related ovario-
leukodystrophy: Clinical and neuroimaging features of three new
cases. Acta Neurol Scand. 2018;138(4):278–83. https://​doi.​org/​
10.​1111/​ane.​12954.
47. Hamatani M, Jingami N, Tsurusaki Y, Shimada S, Shimojima
K, Asada-Utsugi M, Yoshinaga K, Uemura N, Yamashita H,
Uemura K, Takahashi R, Matsumoto N, Yamamoto T. The first
Japanese case of leukodystrophy with ovarian failure arising
from novel compound heterozygous AARS2 mutations. J Hum
Genet. 2016;61(10):899–902. https://​doi.​org/​10.​1038/​jhg.​2016.​
64.
48. Krieger M, Roos A, Stendel C, Claeys KG, Sonmez FM, Baudis
M, Bauer P, Bornemann A, de Goede C, Dufke A, Finkel RS,
Goebel HH, Häussler M, Kingston H, Kirschner J, Medne L,
Muschke P, Rivier F, Rudnik-Schöneborn S, Spengler S, Inzana
F, Stanzial F, Benedicenti F, Synofzik M, Lia Taratuto A, Pirra
L, Tay SK, Topaloglu H, Uyanik G, Wand D, Williams D, Zerres
K, Weis J, Senderek J. SIL1 mutations and clinical spectrum in
patients with Marinesco-Sjogren syndrome. Brain. 2013;136(Pt
12):3634–44. https://​doi.​org/​10.​1093/​brain/​awt283.
49. Anttonen A-K, Siintola E, Tranebjaerg L, Iwata NK, Bijlsma
EK, Meguro H, Ichikawa Y, Goto J, Kopra O, Lehesjoki A-E.
Novel SIL1 mutations and exclusion of functional candidate
genes in Marinesco-Sjögren syndrome. Eur J Hum Genet.
2008;16(8):961–9. https://​doi.​org/​10.​1038/​ejhg.​2008.​22.
50. Eriguchi M, Mizuta H, Kurohara K, Fujitake J, Kuroda Y. Iden-
tification of a new homozygous frameshift insertion mutation in
the SIL1 gene in 3 Japanese patients with Marinesco-Sjögren
syndrome. J Neurol Sci. 2008;270(1–2):197–200. https://d​ oi.o​ rg/​
10.​1016/j.​jns.​2008.​02.​012.
51. Reinhold A, Scheer I, Lehmann R, Neumann LM, Michael T,
Varon R, Von Moers A. MR imaging features in Marinesco-
Sjögren syndrome: severe cerebellar atrophy is not an obligatory
finding. AJNR Am J Neuroradiol. 2003;24(5):825–8.
52. Harting I, Blaschek A, Wolf NI, Seitz A, Haupt M, Goebel HH,
Rating D, Sartor K, Ebinger F. T2-hyperintense cerebellar cortex
in Marinesco-Sjögren syndrome. Neurology. 2004;63(12):2448–
9. https://​doi.​org/​10.​1212/​01.​wnl.​00001​47324.​74071.​3e.
53. McLaughlin JF, Pagon RA, Weinberger E, Haas JE. Marinesco-
Sjögren syndrome: clinical and magnetic resonance imaging fea-
tures in three children. Dev Med Child Neurol. 1996;38(4):363–
70. https://d​ oi.o​ rg/1​ 0.1​ 111/j.1​ 469-8​ 749.1​ 996.t​ b1210​ 3.x. Erratum
13

in: Dev Med Child Neurol 1996;38(6):472. Corrected and repub-
lished in: Dev Med Child Neurol. 1996;38(7):636–44.
54. Moreira MC, Klur S, Watanabe M, Németh AH, Le Ber I, Moniz JC,
Tranchant C, Aubourg P, Tazir M, Schöls L, Pandolfo M, Schulz
JB, Pouget J, Calvas P, Shizuka-Ikeda M, Shoji M, Tanaka M,
Izatt L, Shaw CE, M'Zahem A, Dunne E, Bomont P, Benhassine
T, Bouslam N, Stevanin G, Brice A, Guimarães J, Mendonça P,
Barbot C, Coutinho P, Sequeiros J, Dürr A, Warter JM, Koenig M.
Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-
ocular apraxia 2. Nat Genet. 2004;36(3):225–7. https://​doi.​org/​10.​
1038/​ng1303.
55. Anheim M, Monga B, Fleury M, Charles P, Barbot C, Salih
M, Delaunoy JP, Fritsch M, Arning L, Synofzik M, Schöls L,
Sequeiros J, Goizet C, Marelli C, Le Ber I, Koht J, Gazulla J,
De Bleecker J, Mukhtar M, Drouot N, Ali-Pacha L, Benhassine
T, Chbicheb M, M'Zahem A, Hamri A, Chabrol B, Pouget J,
Murphy R, Watanabe M, Coutinho P, Tazir M, Durr A, Brice A,
Tranchant C, Koenig M. Ataxia with oculomotor apraxia type 2:
clinical, biological and genotype/phenotype correlation study of
a cohort of 90 patients. Brain. 2009;132(Pt 10):2688–98. https://​
doi.​org/​10.​1093/​brain/​awp211.
56. Le Ber I, Bouslam N, Rivaud-Péchoux S, Guimarães J, Benomar A,
Chamayou C, Goizet C, Moreira MC, Klur S, Yahyaoui M, Agid Y,
Koenig M, Stevanin G, Brice A, Dürr A. Frequency and phenotypic
spectrum of ataxia with oculomotor apraxia 2: a clinical and genetic
study in 18 patients. Brain. 2004;127(Pt 4):759–67. https://​doi.​org/​
10.​1093/​brain/​awh080.
57. Lynch DR, Braastad CD, Nagan N. Ovarian failure in
ataxia with oculomotor apraxia type 2. Am J Med Genet A.
2007;143A(15):1775–7. https://​doi.​org/​10.​1002/​ajmg.a.​31816.
58. Fogel BL, Lee JY, Perlman S. Aberrant splicing of the sena-
taxin gene in a patient with ataxia with oculomotor apraxia type
2. Cerebellum. 2009 ;8(4):448–53. https://​doi.​org/​10.​1007/​
s12311-​009-​0130-8.
59 Frismand S, Salem H, Panouilleres M, Pélisson D, Jacobs S, Vighetto
A, Cotton F, Tilikete C. MRI findings in AOA2: Cerebellar atrophy
and abnormal iron detection in dentate nucleus. NeuroImage: Clinical.
2013;2:542–8. https://​doi.​org/​10.​1016/j.​nicl.​2013.​03.​018.
60. Nanetti L, Cavalieri S, Pensato V, Erbetta A, Pareyson D, Panzeri
M, Zorzi G, Antozzi C, Moroni I, Gellera C, Brusco A, Mariotti
C. SETX mutations are a frequent genetic cause of juvenile and
adult onset cerebellar ataxia with neuropathy and elevated serum
alpha-fetoprotein. Orphanet J Rare Dis. 2013;8:123. https://​doi.​
org/​10.​1186/​1750-​1172-8-​123.
61. Cocozza S, Pontillo G, De Michele G, Di Stasi M, Guerriero
E, Perillo T, Pane C, De Rosa A, Ugga L, Brunetti A. Conven-
tional MRI findings in hereditary degenerative ataxias: a pictorial
review. Neuroradiology. 2021;63(7):983–99. https://​doi.​org/​10.​
1007/​s00234-​021-​02682-2.
62. Tariq H, Imran R, Naz S. A Novel Homozygous Variant of SETX
Causes Ataxia with Oculomotor Apraxia Type 2. J Clin Neurol.
2018;14(4):498-504. https://​doi.​org/​10.​3988/​jcn.​2018.​14.4.​498.
63. Ronsin S, Hannoun S, Thobois S, Petiot P, Vighetto A, Cot-
ton F, Tilikete C. A new MRI marker of ataxia with oculomo-
tor apraxia. Eur J Radiol. 2019;110:187–92. https://​doi.​org/​10.​
1016/j.​ejrad.​2018.​11.​035.
64. Hikmat O, Tzoulis C, Chong WK, Chentouf L, Klingenberg
C, Fratter C, Carr LJ, Prabhakar P, Kumaraguru N, Gissen P,
Cross JH, Jacques TS, Taanman JW, Bindoff LA, Rahman S.
The clinical spectrum and natural history of early-onset dis-
eases due to DNA polymerase gamma mutations. Genet Med.
2017;19(11):1217–25. https://​doi.​org/​10.​1038/​gim.​2017.​35.
Erratum in: Genet Med. 2019;21(4):1027.
65. Rahman S. Mitochondrial disease and epilepsy. Dev Med Child
Neurol. 2012;54(5):397–406. https://​doi.​org/​10.​1111/j.​1469-​
8749.​2011.​04214.x.
13
The Cerebellum
66. Jha R, Patel H, Dubey R, Goswami JN, Bhagwat C, Saini L,
K Manokaran R, John BM, Kovilapu UB, Mohimen A, Saxena
A, Sondhi V. Clinical and molecular spectrum associated with
Polymerase-γ related disorders. J Child Neurol. 2022;37(4):246–
55. https://​doi.​org/​10.​1177/​08830​73821​10670​65.
67. Saneto RP, Cohen BH, Copeland WC, Naviaux RK. Alpers-Hut-
tenlocher syndrome. Pediatr Neurol. 2013;48(3):167–78. https://​
doi.​org/​10.​1016/j.​pedia​trneu​rol.​2012.​09.​014.
68. Hikmat O, Naess K, Engvall M, Klingenberg C, Rasmussen M,
Tallaksen CM, Brodtkorb E, Ostergaard E, de Coo IFM, Pias-
Peleteiro L, Isohanni P, Uusimaa J, Darin N, Rahman S, Bindoff
LA. Simplifying the clinical classification of polymerase gamma
(POLG) disease based on age of onset; studies using a cohort of
155 cases. J Inherit Metab Dis. 2020;43(4):726–36. https://​doi.​
org/​10.​1002/​jimd.​12211.
69. Béreau M, Anheim M, Echaniz-Laguna A, Magot A, Verny C, Goi-
deau-Sevrain M, Barth M, Amati-Bonneau P, Allouche S, Ayrignac
X, Bédat-Millet AL, Guyant-Maréchal L, Kuntzer T, Ochsner F,
Petiot P, Vial C, Omer S, Sole G, Taieb G, Carvalho N, Tio G,
Kremer S, Acquaviva-Bourdain C, de Camaret BM, Tranchant C.
The wide POLG-related spectrum: An integrated view. J Neurol
Sci. 2016;368:70–6. https://​doi.​org/​10.​1016/j.​jns.​2016.​06.​062.
70. Nicastro N, Ranza E, Antonarakis SE, Horvath J. Pure Pro-
gressive Ataxia and Palatal Tremor (PAPT) Associated with
a New Polymerase Gamma (POLG) Mutation. Cerebellum.
2016;15(6):829–31. https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 12311-0​ 15-0​ 749-6.
71. Henao AI, Pira S, Herrera DA, Vargas SA, Montoya J, Castillo
M. Characteristic brain MRI findings in ataxia-neuropathy spec-
trum related to POLG mutation. Neuroradiol J. 2016;29(1):46–8.
https://​doi.​org/​10.​1177/​19714​00915​621324.
72. Anagnostou ME, Ng YS, Taylor RW, McFarland R. Epilepsy due to
mutations in the mitochondrial polymerase gamma (POLG) gene: A
clinical and molecular genetic review. Epilepsia. 2016;57(10):1531–
45. https://​doi.​org/​10.​1111/​epi.​13508..
73. Synofzik M, Srulijes K, Godau J, Berg D, Schöls L. Charac-
terizing POLG ataxia: clinics, electrophysiology and imaging.
Cerebellum. 2012;11(4):1002–11. https://​ d oi.​o rg/​1 0.​1 007/​
s12311-​012-​0378-2.
74. Paramasivam A, Venkatapathi C, Sandeep G, Meena AK, Uppin
MS, Mohapatra S, Pitceathly RDS, Thangaraj K. Homozygous
R627W mutations in POLG cause mitochondrial DNA deple-
tion leading to encephalopathy, seizures and stroke-like episodes.
Mitochondrion. 2019;48:78–83. https://​doi.​org/​10.​1016/j.​mito.​
2019.​08.​003.
75. Tzoulis C, Engelsen BA, Telstad W, Aasly J, Zeviani M, Win-
terthun S, Ferrari G, Aarseth JH, Bindoff LA. The spectrum of
clinical disease caused by the A467T and W748S POLG muta-
tions: a study of 26 cases. Brain. 2006;129(7):1685–92. https://​
doi.​org/​10.​1093/​brain/​awl097.
76. Parada-Garza JD, López-Valencia G, Miranda-García LA,
Pérez-García G, Ruiz-Sandoval JL. MRI findings in SANDO
variety of the ataxia-neuropathy spectrum with a novel muta-
tion in POLG (c.3287G>T): A case report. Neuromuscul Disord.
2020;30(7):590–92. https://​doi.​org/​10.​1016/j.​nmd.​2020.​04.​008.
77. Van Goethem G, Luoma P, Rantamäki M, Al Memar A, Kaak-
kola S, Hackman P, Krahe R, Löfgren A, Martin JJ, De Jonghe P,
Suomalainen A, Udd B, Van Broeckhoven C. POLG mutations in
neurodegenerative disorders with ataxia but no muscle involve-
ment. Neurology. 2004;63(7):1251–7. https://​doi.​org/​10.​1212/​
01.​wnl.​00001​40494.​58732.​83.
78. Bender F, Timmann D, van de Warrenburg BP, Adarmes-Gómez AD,
Bender B, Thieme A, Synofzik M, Schöls L. Natural History of Pol-
ymerase Gamma-Related Ataxia. Mov Disord. 2021;36(11):2642–
52. https://​doi.​org/​10.​1002/​mds.​28713.
79. Nuzhnyi E, Seliverstov Y, Klyushnikov S, Krylova T, Tsygankova
P, Bychkov I, Zakharova E, Konovalov R, Fedin P, Abramycheva
The Cerebellum
N, Illarioshkin S. POLG-associated ataxias can represent a sub-
stantial part of recessive and sporadic ataxias in adults. Clin Neu-
rol Neurosurg. 2021;201:106462. https://​doi.​org/​10.​1016/j.​cline​
uro.​2020.​106462.
80. McKelvie P, Marotta R, Thorburn DR, Chin J, Punchihewa S,
Collins S. A case of myelopathy, myopathy, peripheral neuropa-
thy and subcortical grey matter degeneration associated with
recessive compound heterozygous POLG1 mutations. Neuro-
muscul Disord. 2012;22(5):401–5. https://d​ oi.o​ rg/1​ 0.1​ 016/j.n​ md.​
2011.​10.​017.
81. Habek M, Barun B, Adamec I, Mitrović Z, Ozretić D, Brinar VV.
Early-onset ataxia with progressive external ophthalmoplegia
associated with POLG mutation: autosomal recessive mitochon-
drial ataxic syndrome or SANDO? Neurologist. 2012;18(5):287–
9. https://​doi.​org/​10.​1097/​NRL.​0b013​e3182​66f5a6.
82. Uusimaa J, Gowda V, McShane A, Smith C, Evans J, Shrier A,
Narasimhan M, O'Rourke A, Rajabally Y, Hedderly T, Cowan
F, Fratter C, Poulton J. Prospective study of POLG mutations
presenting in children with intractable epilepsy: prevalence and
clinical features. Epilepsia. 2013;54(6):1002–11. https://​doi.​org/​
10.​1111/​epi.​12115.
83. Arkadir D, Meiner V, Karni A, Lossos A. Teaching NeuroIm-
ages: hypertrophic olivary degeneration in a young man with
POLG gene mutation. Neurology. 2015;84(8):e59. https://​doi.​
org/​10.​1212/​WNL.​00000​00000​001287.
84. Kinghorn KJ, Kaliakatsos M, Blakely EL, Taylor RW, Rich P,
Clarke A, Omer S. Hypertrophic olivary degeneration on mag-
netic resonance imaging in mitochondrial syndromes associated
with POLG and SURF1 mutations. J Neurol. 2013;260(1):3–9.
https://​doi.​org/​10.​1007/​s00415-​012-​6564-9.
85. Gu CN, Carr CM, Kaufmann TJ, Kotsenas AL, Hunt CH,
Wood CP. MRI Findings in Nonlesional Hypertrophic Olivary
Degeneration. J Neuroimaging : Off J Am Soc Neuroimaging.
2015;25(5):813–7. https://​doi.​org/​10.​1111/​jon.​12267.
86. Raeder MTL, Reis EP, Campos BM, Zamilute IAG, França
Júnior MC, Reis F. Transaxonal degenerations of cerebellar con-
nections: the value of anatomical knowledge. Arq Neuropsiquiatr.
2020;78(5):301–6. https://d​ oi.o​ rg/1​ 0.1​ 590/0​ 004-2​ 82x20​ 20002​ 1.
87. Tzoulis C, Tran GT, Coxhead J, Bertelsen B, Lilleng PK, Balaf-
kan N, Payne B, Miletic H, Chinnery PF, Bindoff LA. Molecular
pathogenesis of polymerase γ-related neurodegeneration. Ann
Neurol. 2014;76(1):66–81. https://​doi.​org/​10.​1002/​ana.​24185.
88. Tzoulis C, Neckelmann G, Mørk SJ, Engelsen BE, Viscomi C,
Moen G, Ersland L, Zeviani M, Bindoff LA. Localized cerebral
energy failure in DNA polymerase gamma-associated encepha-
lopathy syndromes. Brain. 2010;133(Pt 5):1428–37. https://​doi.​
org/​10.​1093/​brain/​awq067.
89. de Vries MC, Rodenburg RJ, Morava E, van Kaauwen EPM,
ter Laak H, Mullaart RA, Snoeck IN, van Hasselt PM, Hard-
ing P, van den Heuvel LPW, Smeitink JAM. Multiple oxidative
phosphorylation deficiencies in severe childhood multi-sys-
tem disorders due to polymerase gamma (POLG1) mutations.
Eur J Pediatr. 2007;166(3):229–34. https://​doi.​org/​10.​1007/​
s00431-​006-​0234-9.
90. Simon M, Chang RC, Bali DS, Wong LJ, Peng Y, Abdenur
JE. Abnormalities in glycogen metabolism in a patient with
alpers' syndrome presenting with hypoglycemia. JIMD Rep.
2014;14:29–35. https://​doi.​org/​10.​1007/​8904_​2013_​280.
91. Altassan R, Péanne R, Jaeken J, Barone R, Bidet M, Borgel D,
Brasil S, Cassiman D, Cechova A, Coman D, Corral J, Correia
J, de la Morena-Barrio ME, de Lonlay P, Dos Reis V, Ferreira
CR, Fiumara A, Francisco R, Freeze H, Funke S, Gardeitchik T,
Gert M, Girad M, Giros M, Grünewald S, Hernández-Caselles
T, Honzik T, Hutter M, Krasnewich D, Lam C, Lee J, Lefeber D,
Marques-de-Silva D, Martinez AF, Moravej H, Õunap K, Pascoal
C, Pascreau T, Patterson M, Quelhas D, Raymond K, Sarkhail P,
Schiff M, Seroczyńska M, Serrano M, Seta N, Sykut-Cegielska
J, Thiel C, Tort F, Vals MA, Videira P, Witters P, Zeevaert R,
Morava E. International clinical guidelines for the management
of phosphomannomutase 2-congenital disorders of glycosyla-
tion: Diagnosis, treatment and follow up. J Inherit Metab Dis.
2019;42(1):5–28. https://​doi.​org/​10.​1002/​jimd.​12024. Erratum
in: J Inherit Metab Dis. 2019;42(3):577.
92. Al-Maawali AA, Miller E, Schulze A, Yoon G, Blaser SI. Sub-
cutaneous fat pads on body MRI — an early sign of congenital
disorder of glycosylation PMM2-CDG (CDG1a). Pediatr Radiol.
2014;44(2):222–5. https://​doi.​org/​10.​1007/​s00247-​013-​2782-2.
93. Giurgea I, Michel A, Le Merrer M, Seta N, de Lonlay P. Under-
diagnosis of mild congenital disorders of glycosylation type Ia.
Pediatr Neurol. 2005;32(2):121–3. https://​doi.​org/​10.​1016/j.​
pedia​trneu​rol.​2004.​06.​021.
94. Pancho C, Garcia-Cazorla A, Varea V, Artuch R, Ferrer I, Vilas-
eca MA, Briones P, Campistol J. Congenital disorder of glyco-
sylation type Ia revealed by hypertransaminasemia and failure to
thrive in a young boy with normal neurodevelopment. J Pediatr
Gastroenterol Nutr. 2005;40(2):230–2. https://​doi.​org/​10.​1097/​
00005​176-​20050​2000-​00030.
95. Coman D, Klingberg S, Morris D, McGill J, Mercer H. Con-
genital disorder of glycosylation type Ia in a 6-year-old girl with
a mild intellectual phenotype: two novel PMM2 mutations. J
Inherit Metab Dis. 2005;28(6):1189–90. https://d​ oi.o​ rg/1​ 0.1​ 007/​
s10545-​005-​0166-y.
96. Drouin-Garraud V, Belgrand M, Grünewald S, Seta N, Dacher
J-N, Hénocq A, Matthijs G, Cormier-Daire V, Frébourg T, Sau-
gier-Veber P. Neurological presentation of a congenital disorder
of glycosylation CDG-Ia: implications for diagnosis and genetic
counseling. Am J Med Genet. 2001;101(1):46–9. https://​doi.​org/​
10.​1002/​ajmg.​1298.
97. Schade van Westrum SM, Nederkoorn PJ, Schuurman PR,
Vulsma T, Duran M, Poll-The BT. Skeletal dysplasia and mye-
lopathy in congenital disorder of glycosylation type IA. J Pediatr.
2006;148(1):115–7. https://d​ oi.o​ rg/1​ 0.1​ 016/j.j​ peds.2​ 005.0​ 8.0​ 48.
98. Al Teneiji A, Bruun TUJ, Sidky S, Cordeiro D, Cohn RD, Men-
doza-Londono R, Moharir M, Raiman J, Siriwardena K, Kyriako-
poulou L, Mercimek-Mahmutoglu S. Phenotypic and genotypic
spectrum of congenital disorders of glycosylation type I and type
II. Mol Genet Metab. 2017;120(3):235–42. https://​doi.​org/​10.​
1016/j.​ymgme.​2016.​12.​014.
99. Serrano M. Stroke-Like Episodes in PMM2-CDG: When the
Lack of Other Evidence Is the Only Evidence. Front Pediatr.
2021;9:717864. https://​doi.​org/​10.​3389/​fped.​2021.​717864.
100. Grünert SC, Marquardt T, Lausch E, Fuchs H, Thiel C, Sutter M,
Schumann A, Hannibal L, Spiekerkoetter U. Unsuccessful intra-
venous D-mannose treatment in PMM2-CDG. Orphanet J Rare
Dis. 2019;14(1):231. https://​doi.​org/​10.​1186/​s13023-​019-​1213-3.
101. Vals M-A, Morava E, Teeäär K, Zordania R, Pajusalu S, Lefeber
DJ, Õunap K. Three families with mild PMM2-CDG and normal
cognitive development. Am J Med Genet A. 2017;173(6):1620–
4. https://​doi.​org/​10.​1002/​ajmg.a.​38235.
102. Serrano NL, De Diego V, Cuadras D, Martinez Monseny AF,
Velázquez-Fragua R, López L, Felipe A, Gutiérrez-Solana LG,
Macaya A, Pérez-Dueñas B, Serrano M; CDG Spanish-Consor-
tium. A quantitative assessment of the evolution of cerebellar
syndrome in children with phosphomannomutase-deficiency
(PMM2-CDG). Orphanet J Rare Dis. 2017;12(1):155. https://​
doi.​org/​10.​1186/​s13023-​017-​0707-0.
103. Casado M, O'Callaghan MM, Montero R, Pérez-Cerda C,
Pérez B, Briones P, Quintana E, Muchart J, Aracil A, Pineda
M, Artuch R. Mild clinical and biochemical phenotype in two
patients with PMM2-CDG (congenital disorder of glycosylation
Ia). Cerebellum. 2012;11(2):557–63. https://​doi.​org/​10.​1007/​
s12311-​011-​0313-y.
13

104. Mostile G, Barone R, Nicoletti A, Rizzo R, Martinelli D, Sturiale
L, Fiumara A, Jankovic J, Zappia M. Hyperkinetic movement
disorders in congenital disorders of glycosylation. Eur J Neurol.
2019;26(9):1226–34. https://​doi.​org/​10.​1111/​ene.​14007.
105. de Diego V, Martínez-Monseny AF, Muchart J, Cuadras D,
Montero R, Artuch R, Pérez-Cerdá C, Pérez B, Pérez-Dueñas
B, Poretti A, Serrano M; Collaborators of the CDG Spanish-
Consortium. Longitudinal volumetric and 2D assessment of
cerebellar atrophy in a large cohort of children with phospho-
mannomutase deficiency (PMM2-CDG). J Inherit Metab Dis.
2017;40(5):709–13. https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 10545-0​ 17-0​ 028-4.
Erratum in: J Inherit Metab Dis. 2017.
106. Monin M-L, Mignot C, De Lonlay P, Héron B, Masurel A,
Mathieu-Dramard M, Lenaerts C, Thauvin C, Gérard M, Roze
E, Jacquette A, Charles P, de Baracé C, Drouin-Garraud V, Van
Kien PK, Cormier-Daire V, Mayer M, Ogier H, Brice A, Seta
N, Héron D. 29 French adult patients with PMM2-congenital
disorder of glycosylation: outcome of the classical pediatric phe-
notype and depiction of a late-onset phenotype. Orphanet J Rare
Dis. 2014;9(1):207. https://​doi.​org/​10.​1186/​s13023-​014-​0207-4.
107. Serrano M, de Diego V, Muchart J, Cuadras D, Felipe A, Macaya
A, Velázquez R, Poo MP, Fons C, O'Callaghan MM, García-
Cazorla A, Boix C, Robles B, Carratalá F, Girós M, Briones P,
Gort L, Artuch R, Pérez-Cerdá C, Jaeken J, Pérez B, Pérez-Due-
ñas B. Phosphomannomutase deficiency (PMM2-CDG): ataxia
and cerebellar assessment. Orphanet J Rare Dis. 2015;10:138.
https://​doi.​org/​10.​1186/​s13023-​015-​0358-y.
108. Pettinato F, Mostile G, Battini R, Martinelli D, Madeo A, Biamino
E, Frattini D, Garozzo D, Gasperini S, Parini R, Sirchia F, Sor-
tino G, Sturiale L, Matthijs G, Morrone A, Di Rocco M, Rizzo
R, Jaeken J, Fiumara A, Barone R. Clinical and radiological cor-
relates of activities of daily living in cerebellar atrophy caused by
PMM2 mutations (PMM2-CDG). Cerebellum. 2021;20(4):596–
605. https://​doi.​org/​10.​1007/​s12311-​021-​01242-x.
109. Barone R, Carrozzi M, Parini R, Battini R, Martinelli D, Elia M,
Spada M, Lilliu F, Ciana G, Burlina A, Leuzzi V, Leoni M, Stu-
riale L, Matthijs G, Jaeken J, Di Rocco M, Garozzo D, Fiumara
A. A nationwide survey of PMM2-CDG in Italy: high frequency
of a mild neurological variant associated with the L32R muta-
tion. J Neurol. 2015;262(1):154–64. https://​doi.​org/​10.​1007/​
s00415-​014-​7549-7.
110. Schiff M, Roda C, Monin ML, Arion A, Barth M, Bednarek N,
Bidet M, Bloch C, Boddaert N, Borgel D, Brassier A, Brice A,
Bruneel A, Buissonnière R, Chabrol B, Chevalier MC, Cormier-
Daire V, De Barace C, De Maistre E, De Saint-Martin A, Dorison
N, Drouin-Garraud V, Dupré T, Echenne B, Edery P, Feillet F,
Fontan I, Francannet C, Labarthe F, Gitiaux C, Héron D, Hully
M, Lamoureux S, Martin-Coignard D, Mignot C, Morin G, Pas-
creau T, Pincemaille O, Polak M, Roubertie A, Thauvin-Robinet
C, Toutain A, Viot G, Vuillaumier-Barrot S, Seta N, De Lonlay P.
Clinical, laboratory and molecular findings and long-term follow-
up data in 96 French patients with PMM2-CDG (phosphoman-
nomutase 2-congenital disorder of glycosylation) and review of
the literature. J Med Genet. 2017;54(12):843–51. https://d​ oi.o​ rg/​
10.​1136/​jmedg​enet-​2017-​104903.
111. Coorg R, Lotze TE. Child Neurology: a case of PMM2-CDG
(CDG 1a) presenting with unusual eye movements. Neurology.
2012;79(15):e131-3. https://​doi.​org/​10.​1212/​WNL.​0b013​e3182​
6e2617.
112. Feraco P, Mirabelli-Badenier M, Severino M, Alpigiani MG, Di
Rocco M, Biancheri R, Rossi A. The shrunken, bright cerebel-
lum: a characteristic MRI finding in congenital disorders of gly-
cosylation type 1a. AJNR Am J Neuroradiol. 2012;33(11):2062–
7. https://​doi.​org/​10.​3174/​ajnr.​A3151.
113. Farmania R, Jain P, Sharma S, Aneja S. Unusual Presenta-
tion of PMM2-Congenital Disorder of Glycosylation With
13
The Cerebellum
Isolated Strokelike Episodes in a Young Girl. J Child Neurol.
2019;34(7):410–4. https://​doi.​org/​10.​1177/​08830​73819​833543.
114. Dinopoulos A, Mohamed I, Jones B, Rao S, Franz D, deGrauw T.
Radiologic and neurophysiologic aspects of stroke-like episodes
in children with congenital disorder of glycosylation type Ia.
Pediatrics. 2007;119(3):e768–72. https://​doi.​org/​10.​1542/​peds.​
2006-​0763.
115. Izquierdo-Serra M, Martínez-Monseny AF, López L, Carrillo-
García J, Edo A, Ortigoza-Escobar JD, García Ó, Cancho-Can-
dela R, Carrasco-Marina ML, Gutiérrez-Solana LG, Cuadras
D, Muchart J, Montero R, Artuch R, Pérez-Cerdá C, Pérez B,
Pérez-Dueñas B, Macaya A, Fernández-Fernández JM, Serrano
M. Stroke-Like Episodes and Cerebellar Syndrome in Phospho-
mannomutase Deficiency (PMM2-CDG): Evidence for Hypogly-
cosylation-Driven Channelopathy. Int J Mol Sci. 2018;19(2):619.
https://​doi.​org/​10.​3390/​ijms1​90206​19.
116. Pearl PL, Krasnewich D. Neurologic course of congenital disor-
ders of glycosylation. J Child Neurol. 2001;16(6):409–13. https://​
doi.​org/​10.​1177/​08830​73801​01600​604.
117. Ishikawa N, Tajima G, Ono H, Kobayashi M. Different neurora-
diological findings during two stroke-like episodes in a patient
with a congenital disorder of glycosylation type Ia. Brain Dev.
2009;31(3):240–3. https://​doi.​org/​10.​1016/j.​brain​dev.​2008.​03.​
012.
118. van Baalen A, Stephani U, Rohr A. Increased brain lactate dur-
ing stroke-like episode in a patient with congenital disorder of
glycosylation type Ia. Brain Dev. 2009 ;31(2):183. https://​doi.​
org/​10.​1016/j.​brain​dev.​2008.​08.​014.
119. Takanashi J, Osaka H, Saitsu H, Sasaki M, Mori H, Shibay-
ama H, Tanaka M, Nomura Y, Terao Y, Inoue K, Matsumoto
N, Barkovich AJ. Different patterns of cerebellar abnormality
and hypomyelination between POLR3A and POLR3B mutations.
Brain Dev. 2014;36(3):259–63. https://​doi.​org/​10.​1016/j.​brain​
dev.​2013.​03.​006.
120. Bernard G, Chouery E, Putorti ML, Tétreault M, Takanohashi
A, Carosso G, Clément I, Boespflug-Tanguy O, Rodriguez D,
Delague V, Abou Ghoch J, Jalkh N, Dorboz I, Fribourg S, Teich-
mann M, Megarbane A, Schiffmann R, Vanderver A, Brais B.
Mutations of POLR3A encoding a catalytic subunit of RNA
polymerase Pol III cause a recessive hypomyelinating leukod-
ystrophy. Am J Hum Genet. 2011;89(3):415–23. https://​doi.​
org/​10.​1016/j.​ajhg.​2011.​07.​014. Erratum in: Am J Hum Genet.
2012;91(5):972.
121. Cayami FK, La Piana R, van Spaendonk RM, Nickel M, Bley
A, Guerrero K, Tran LT, van der Knaap MS, Bernard G, Wolf
NI. POLR3A and POLR3B Mutations in Unclassified Hypomy-
elination. Neuropediatrics. 2015;46(3):221–8. https://d​ oi.o​ rg/1​ 0.​
1055/s-​0035-​15501​48.
122. La Piana R, Tonduti D, Gordish Dressman H, Schmidt JL,
Murnick J, Brais B, Bernard G, Vanderver A. Brain magnetic
resonance imaging (MRI) pattern recognition in Pol III-related
leukodystrophies. J Child Neurol. 2014;29(2):214–20. https://​
doi.​org/​10.​1177/​08830​73813​503902.
123. Wolf NI, Vanderver A, van Spaendonk RM, Schiffmann R, Brais
B, Bugiani M, Sistermans E, Catsman-Berrevoets C, Kros JM,
Pinto PS, Pohl D, Tirupathi S, Strømme P, de Grauw T, Fribourg
S, Demos M, Pizzino A, Naidu S, Guerrero K, van der Knaap
MS, Bernard G; 4H Research Group. Clinical spectrum of 4H
leukodystrophy caused by POLR3A and POLR3B mutations.
Neurology. 2014;83(21):1898–905. https://​doi.​org/​10.​1212/​
WNL.​00000​00000​001002.
124. Steenweg ME, Vanderver A, Blaser S, Bizzi A, de Koning TJ,
Mancini GMS, van Wieringen WN, Barkhof F, Wolf NI, van
der Knaap MS. Magnetic resonance imaging pattern recogni-
tion in hypomyelinating disorders. Brain. 2010;133(10):2971–82.
https://​doi.​org/​10.​1093/​brain/​awq257.
The Cerebellum
125. Zanette V, Reyes A, Johnson M, do Valle D, Robinson AJ, Mon-
teiro V, Telles BA, L R Souza R, S F Santos ML, Benincá C,
Zeviani M. Neurodevelopmental regression, severe generalized
dystonia, and metabolic acidosis caused by POLR3A mutations.
Neurol Genet. 2020;6(6):e521. https://​doi.​org/​10.​1212/​NXG.​
00000​00000​000521.
126. Azmanov DN, Siira SJ, Chamova T, Kaprelyan A, Guergueltch-
eva V, Shearwood AJ, Liu G, Morar B, Rackham O, Bynevelt
M, Grudkova M, Kamenov Z, Svechtarov V, Tournev I, Kalay-
djieva L, Filipovska A. Transcriptome-wide effects of a POLR3A
gene mutation in patients with an unusual phenotype of striatal
involvement. Hum Mol Genet. 2016;25(19):4302–14. https://d​ oi.​
org/​10.​1093/​hmg/​ddw263.
127. Harting I, Al-Saady M, Krägeloh-Mann I, Bley A, Hempel M,
Bierhals T, Karch S, Moog U, Bernard G, Huntsman R, van
Spaendonk RML, Vreeburg M, Rodríguez-Palmero A, Pujol A,
van der Knaap MS, Pouwels PJW, Wolf NI. POLR3A variants
with striatal involvement and extrapyramidal movement disor-
der. Neurogenetics. 2020;21(2):121–33. https://​doi.​org/​10.​1007/​
s10048-​019-​00602-4.
128. La Piana R, Cayami FK, Tran LT, Guerrero K, van Spaendonk
R, Õunap K, Pajusalu S, Haack T, Wassmer E, Timmann D,
Mierzewska H, Poll-Thé BT, Patel C, Cox H, Atik T, Onay H,
Ozkınay F, Vanderver A, van der Knaap MS, Wolf NI, Bernard
G. Diffuse hypomyelination is not obligate for POLR3-related
disorders. Neurology. 2016;86(17):1622–6. https://​doi.​org/​10.​
1212/​WNL.​00000​00000​002612.
129. Minnerop M, Kurzwelly D, Wagner H, Soehn AS, Reichbauer
J, Tao F, Rattay TW, Peitz M, Rehbach K, Giorgetti A, Pyle A,
Thiele H, Altmüller J, Timmann D, Karaca I, Lennarz M, Baets
J, Hengel H, Synofzik M, Atasu B, Feely S, Kennerson M, Sten-
del C, Lindig T, Gonzalez MA, Stirnberg R, Sturm M, Roeske
S, Jung J, Bauer P, Lohmann E, Herms S, Heilmann-Heimbach
S, Nicholson G, Mahanjah M, Sharkia R, Carloni P, Brüstle O,
Klopstock T, Mathews KD, Shy ME, de Jonghe P, Chinnery PF,
Horvath R, Kohlhase J, Schmitt I, Wolf M, Greschus S, Amunts
K, Maier W, Schöls L, Nürnberg P, Zuchner S, Klockgether T,
Ramirez A, Schüle R. Hypomorphic mutations in POLR3A are
a frequent cause of sporadic and recessive spastic ataxia. Brain.
2017;140(6):1561–78. https://​doi.​org/​10.​1093/​brain/​awx095.
Erratum in: Brain. 2017 Dec 9.
130. Barrett TG, Bundey SE. Wolfram (DIDMOAD) syndrome. J Med
Genet. 1997;34(10):838–41. https://​doi.​org/​10.​1136/​jmg.​34.​10.​
838.
131. Das L, Rai A, Mavuduru R, Vaiphei K, Sharma A, Gupta V,
Bhadada SK, Lodha S, Panda N, Bhansali A, Singh P, Dutta P.
Wolfram syndrome: clinical and genetic profiling of a cohort
from a tertiary care centre with characterization of the primary
gonadal failure. Endocrine. 2020;69(2):420–9. https://​doi.​org/​
10.​1007/​s12020-​020-​02320-6.
132. Pakdemirli E, Karabulut N, Bir LS, Sermez Y. Cranial magnetic
resonance imaging of Wolfram (DIDMOAD) syndrome. Austra-
las Radiol. 2005;49(2):189–91. https://​doi.​org/​10.​1111/j.​1440-​
1673.​2005.​01420.x.
133. Ito S, Sakakibara R, Hattori T. Wolfram syndrome presenting
marked brain MR imaging abnormalities with few neurologic
abnormalities. AJNR Am J Neuroradiol. 2007;28(2):305–6.
134. Scolding NJ, Kellar-Wood HF, Shaw C, Shneerson JM, Antoun
N. Wolfram syndrome: hereditary diabetes mellitus with brain-
stem and optic atrophy. Ann Neurol. 1996;39(3):352–60. https://​
doi.​org/​10.​1002/​ana.​41039​0312.
135. Ari Ş, Keklíkçí U, Çaça İ, Ünlü K, Kayabaşi H. Wolfram syn-
drome: case report and review of the literature. Compr Ther.
2007;33(1):18–20. https://​doi.​org/​10.​1007/​s12019-​007-​0007-z.
136. Chaussenot A, Bannwarth S, Rouzier C, Vialettes B, Mka-
dem SA, Chabrol B, Cano A, Labauge P, Paquis-Flucklinger
V. Neurologic features and genotype-phenotype correlation in
Wolfram syndrome. Ann Neurol. 2011;69(3):501–8. https://​doi.​
org/​10.​1002/​ana.​22160.
137. Labauge P, Renard D, Chaussenot A, Paquis-Flucklinger V. Neu-
rological picture. Wolfram syndrome associated with leukoen-
cephalopathy. J Neurol Neurosurg Psychiatry. 2010;81(8):928.
https://​doi.​org/​10.​1136/​jnnp.​2009.​185579.
138. Hershey T, Lugar HM, Shimony JS, Rutlin J, Koller JM, Perantie
DC, Paciorkowski AR, Eisenstein SA, Permutt MA; Washington
University Wolfram Study Group. Early brain vulnerability in
Wolfram syndrome. PLoS One. 2012;7(7):e40604. https://​doi.​
org/​10.​1371/​journ​al.​pone.​00406​04.
139. La Morgia C, Maresca A, Amore G, Gramegna LL, Carbonelli
M, Scimonelli E, Danese A, Patergnani S, Caporali L, Tagli-
avini F, Del Dotto V, Capristo M, Sadun F, Barboni P, Savini
G, Evangelisti S, Bianchini C, Valentino ML, Liguori R, Tonon
C, Giorgi C, Pinton P, Lodi R, Carelli V. Calcium mishandling
in absence of primary mitochondrial dysfunction drives cellular
pathology in Wolfram Syndrome. Sci Rep. 2020;10(1):4785.
https://​doi.​org/​10.​1038/​s41598-​020-​61735-3. Erratum in: Sci
Rep. 2020;10(1):10398.
140. Samara A, Lugar HM, Hershey T, Shimony JS. Longitudinal
Assessment of Neuroradiologic Features in Wolfram Syndrome.
AJNR Am J Neuroradiol. 2020;41(12):2364–9. https://​doi.​org/​
10.​3174/​ajnr.​A6831.
141. Gocmen R, Guler E. Teaching NeuroImages: MRI of brain
findings of Wolfram (DIDMOAD) syndrome. Neurology.
2014;83(24):e213–4. https://​doi.​org/​10.​1212/​WNL.0​ 0000​00000​
001082.
142. Galluzzi P, Filosomi G, Vallone IM, Bardelli AM, Venturi C.
MRI of Wolfram syndrome (DIDMOAD). Neuroradiology.
1999;41(10):729–31. https://​doi.​org/​10.​1007/​s0023​40050​832.
143. Anheim M, Tranchant C, Koenig M. The autosomal recessive
cerebellar ataxias. N Engl J Med. 2012;366(7):636–46. https://​
doi.​org/​10.​1056/​NEJMr​a1006​610.
144. Sardanelli F, Parodi RC, Ottonello C, Renzetti P, Saitta S, Lig-
nana E, Mancardi GL. Cranial MRI in ataxia-telangiectasia. Neu-
roradiology. 1995;37(1):77–82. https://​doi.​org/​10.​1007/​BF005​
88526.
145. Tavani F, Zimmerman RA, Berry GT, Sullivan K, Gatti R, Bing-
ham P. Ataxia-telangiectasia: the pattern of cerebellar atrophy
on MRI. Neuroradiology. 2003;45(5):315–9. https://​doi.​org/​10.​
1007/​s00234-​003-​0945-9.
146. Perucca G, Leboucq N, Roubertie A, Rivier F, Menjot N, Val-
entini C, Bonafe A. Role of neuroimaging in the diagnosis
of hereditary cerebellar ataxias in childhood. J Neuroradiol.
2016;43(3):176–85. https://​doi.​org/​10.​1016/j.​neurad.​2016.​03.​
006.
147. Habek M, Brinar VV, Rados M, Zadro I, Zarković K. Brain
MRI abnormalities in ataxia-telangiectasia. Neurologist.
2008;14(3):192–5. https://​doi.​org/​10.​1097/​NRL.​0b013​e3181​
5fa5a7.
148. Lin DD, Barker PB, Lederman HM, Crawford TO. Cerebral
abnormalities in adults with ataxia-telangiectasia. AJNR Am J
Neuroradiol. 2014;35(1):119-23. https://​doi.​org/​10.​3174/​ajnr.​
A3646.
149. Kieslich M, Hoche F, Reichenbach J, Weidauer S, Porto L, Vlaho
S, Schubert R, Zielen S. Extracerebellar MRI-lesions in ataxia
telangiectasia go along with deficiency of the GH/IGF-1 axis,
markedly reduced body weight, high ataxia scores and advanced
age. Cerebellum. 2010;9(2):190–7. https://​doi.​org/​10.​1007/​
s12311-​009-​0138-0.
150. Ahmed O, Felimban Y, Almehdar A. T cell ALL in a child with
Ataxia telangiectasia; diagnosis and management challenges.
Hematology. 2021;26(1):348–54. https://​doi.​org/​10.​1080/​16078​
454.​2021.​19087​25.
13

151. Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R,
Hills J, Grigsby J, Gage B, Hagerman PJ. Intention tremor, par-
kinsonism, and generalized brain atrophy in male carriers of frag-
ile X. Neurology. 2001;57(1):127–30. https://​doi.​org/​10.​1212/​
wnl.​57.1.​127.
152. Hall DA, O'keefe JA. Fragile x-associated tremor ataxia syndrome:
the expanding clinical picture, pathophysiology, epidemiology,
and update on treatment. Tremor Other Hyperkinet Mov (N Y).
2012;2:tre-02-56-352-1. https://​doi.​org/​10.​7916/​D8HD7​TDS.
153. Hagerman PJ, Hagerman RJ. The fragile-X premutation: a matur-
ing perspective. Am J Hum Genet. 2004;74(5):805–16. https://​
doi.​org/​10.​1086/​386296.
154. Jacquemont S, Hagerman RJ, Leehey M, Grigsby J, Zhang
L, Brunberg JA, Greco C, Des Portes V, Jardini T, Levine R,
Berry-Kravis E, Brown WT, Schaeffer S, Kissel J, Tassone F,
Hagerman PJ. Fragile X premutation tremor/ataxia syndrome:
molecular, clinical, and neuroimaging correlates. Am J Hum
Genet. 2003;72(4):869–78. https://​doi.​org/​10.​1086/​374321.
155. Hall DA, Birch RC, Anheim M, Jønch AE, Pintado E, O'Keefe
J, Trollor JN, Stebbins GT, Hagerman RJ, Fahn S, Berry-Kravis
E, Leehey MA. Emerging topics in FXTAS. J Neurodev Disord.
2014;6(1):31. https://​doi.​org/​10.​1186/​1866-​1955-6-​31. Erratum
in: J Neurodev Disord. 2015;7(1):13.
156. Leehey MA. Fragile X-associated tremor/ataxia syndrome:
clinical phenotype, diagnosis, and treatment. J Investig Med.
2009;57(8):830–6. https://​doi.​org/​10.​2310/​JIM.​0b013​e3181​
af59c4.
157. Okamoto K, Tokiguchi S, Furusawa T, Ishikawa K, Quardery
AF, Shinbo S, Sasai K. MR features of diseases involving bilat-
eral middle cerebellar peduncles. AJNR Am J Neuroradiol.
2003;24(10):1946–54.
13
The Cerebellum
158. Muzar Z, Lozano R. Current research, diagnosis, and treatment of
fragile X-associated tremor/ataxia syndrome. Intractable Rare Dis
Res. 2014;3(4):101–9. https://​doi.​org/​10.​5582/​irdr.​2014.​01029.
159. Hall DA, Robertson E, Shelton AL, Losh MC, Mila M, Moreno
EG, Gomez-Anson B, Martínez-Cerdeño V, Grigsby J, Lozano
R, Hagerman R, Maria LS, Berry-Kravis E, O’Keefe JA. Update
on the clinical, radiographic, and neurobehavioral manifestations
in FXTAS and FMR1 premutation carriers. The Cerebellum.
2016;15(5):578–86. https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 12311-0​ 16-0​ 799-4.
160. Apartis E, Blancher A, Meissner WG, Guyant-Maréchal L,
Maltête D, De Broucker T, Legrand AP, Bouzenada H, Thanh
HT, Sallansonnet-Froment M, Wang A, Tison F, Roué-Jagot
C, Sedel F, Charles P, Whalen S, Héron D, Thobois S, Poisson
A, Lesca G, Ouvrard-Hernandez AM, Fraix V, Palfi S, Habert
MO, Gaymard B, Dussaule JC, Pollak P, Vidailhet M, Durr
A, Barbot JC, Gourlet V, Brice A, Anheim M. FXTAS: new
insights and the need for revised diagnostic criteria. Neurology.
2012;79(18):1898–907. https://​doi.​org/​10.​1212/​WNL.​0b013​
e3182​71f7ff.
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