cerebellar atrophy

Myopathy, Mitochondrial Anomalies, and Ataxia

Clinical Characteristics
Ocular Features: 

Ocular findings are variable.  One of three individuals with compound heterozygous mutations had a pigmentary retinopathy with pallor of the optic nerve but no visual abnormalities.  Her sister had only optic nerve pallor.  The eyes are described as "small" and "close-set".

No ocular findings were reported for the family with autosomal dominant inheritance.

Systemic Features: 

Ataxia, short stature, and gait difficulties from an early age are consistent findings.  Some patients are never able to walk.  Motor development is generally delayed.  Truncal and limb ataxia is a feature.  Some degree of intellectual disability is generally present and speech is often delayed.  

The face is long with a myopathic appearance.  Both micrognathia and a prominent jaw may be seen.  The palate is highly arched.  Patients are described as hypotonic and there is generalized muscle weakness both proximal and distal.  Distal sensory impairment has been described in the family with presumed dominant inheritance and there may be psychiatric symptoms of anxiety, depression, and schizophrenia.  Dysmetria with dysdiadochokinesis is often present and a fine intention tremor has been observed.

Mitochondria in fibroblasts exhibit abnormal dynamics and occur in a fragmented network.  Muscle biopsies reveal changes consistent with myopathy.  Serum creatine kinase may be elevated.

Genetics

Compound heterozygous mutations in the MSTO1 gene (1q22) have been found in two families with 3 affected individuals suggesting autosomal recessive inheritance.  In a third family, heterozygous mutations in the same gene were found in a mother and 3 of her adult children, consistent with autosomal dominant transmission.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Neurodevelopmental Disorder, Mitochondrial, with Abnormal Movements and Lactic Acidosis

Clinical Characteristics
Ocular Features: 

Optic atrophy is sometimes present.  Nystagmus, and strabismus are seen in some patients.  A pigmentary retinopathy was found in one individual.

Systemic Features: 

This is a clinically heterogeneous disorder with extensive neurological deficits.  Patients have feeding and swallowing difficulties from the neonatal period.  There is intrauterine growth retardation and postnatally patients usually exhibit psychomotor delays and intellectual disabilities.  Some develop seizures and few achieve normal developmental milestones.  Axial hypotonia is present from early infancy and most patients have muscle weakness and atrophy.  However, there may be spastic quadriplegia which is often associated with dysmetria, tremor, and athetosis.  Ataxia eventually develops in most patients. 

Brain imaging shows cerebral and cerebellar atrophy, enlarged ventricles, white matter defects, and delayed myelination. 

Incomplete metabolic studies suggest there may be abnormalities in mitochondrial oxidative phosphorylation activity in at least some tissues.  Most patients have an elevated serum lactate.

Death in childhood is common.

Genetics

Homozygous and compound heterozygous mutations in the WARS2 gene have been found in several families with this condition.  The considerable variation in the phenotype may at least partially be explained by the fact that an additional variant in the W13G gene is sometimes present which impairs normal localization of the WARS2 gene product within mitochondria.

The transmission pattern in several families is consistent with autosomal recessive inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for the general condition.

References
Article Title: 

Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy

Wortmann SB, Timal S, Venselaar H, Wintjes LT, Kopajtich R, Feichtinger RG, Onnekink C, Muhlmeister M, Brandt U, Smeitink JA, Veltman JA, Sperl W, Lefeber D, Pruijn G, Stojanovic V, Freisinger P, V Spronsen F, Derks TG, Veenstra-Knol HE, Mayr JA, Rotig A, Tarnopolsky M, Prokisch H, Rodenburg RJ. Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy. Hum Mutat. 2017 Dec;38(12):1786-1795.

PubMed ID: 
28905505

Spinocerebellar Ataxia 37

Clinical Characteristics
Ocular Features: 

 Abnormal ocular movements are common, beginning with dysmetric vertical saccades and irregularities of vertical pursuit, with later development of irregular horizontal tracking movements.  Nystagmus is sometimes present. 

Two otherwise asymptomatic individuals with dysmetric vertical saccades and irregular vertical pursuit movements had normal horizontal pursuit movements at the ages of 32 and 40 years and were found to have the SCA37 haplotype.   

Systemic Features: 

The mean age of onset in is about 50 years with signs of dysarthria and a clumsy gait.  Other more variable findings include truncal ataxia, dysmetria, and sometimes dysphagia.  Slow progression of signs may lead to eventual wheelchair dependence within one or two decades of disease onset.  Brain imaging reveals cerebellar atrophy with sparing of the brainstem.

Genetics

Heterozygous mutations in the DAB1 gene (1p32.2) are responsible for this disorder.   This disorder of adult onset has been described in several families living on the Iberian peninsula.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia

Seixas AI, Loureiro JR, Costa C, Ordonez-Ugalde A, Marcelino H, Oliveira CL, Loureiro JL, Dhingra A, Brandao E, Cruz VT, Timoteo A, Quintans B, Rouleau GA, Rizzu P, Carracedo A, Bessa J, Heutink P, Sequeiros J, Sobrido MJ, Coutinho P, Silveira I. A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia. Am J Hum Genet. 2017 Jul 6;101(1):87-103.

PubMed ID: 
28686858

Spastic Ataxia 8, Autosomal Recessive, with Hypomyelinating Leukodystrophy

Clinical Characteristics
Ocular Features: 

Reported ocular signs are limited to abnormal eye movements.  In other forms of spastic ataxia, nystagmus is evident in association with optic atrophy but no fundus examinations are reported in the 3 families with SPAX8.  Hypometric saccades and limited upgaze have also been found in these families.

Systemic Features: 

First signs and symptoms occur sometime in the first 5 years of life and often in the first year.   In 6 of 7 reported patients the presenting sign was nystagmus but one individual with reported onset of disease at age 5 years presented with ataxia.  Cerebellar signs, both truncal and limb, are usually present and the majority of individuals have evidence of dystonia.  Likewise, pyramidal signs are nearly always present.  Cerebellar dysarthria and titubation are often present with dystonic posturing and torticollis. 

Brain MRIs usually reveal cerebellar atrophy and widespread hypomyelination.  Two individuals in a single family had severe global psychomotor delays as well.  No sensory deficits were reported.  This disorder is progressive and patients in adulthood may require the use of a wheelchair.

Genetics

Homozygous mutations in the NKX6-2 (NKX6-2) gene (10q26.3) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for the general condition.

References
Article Title: 

Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination

Chelban V, Patel N, Vandrovcova J, Zanetti MN, Lynch DS, Ryten M, Botia JA, Bello O, Tribollet E, Efthymiou S, Davagnanam I; SYNAPSE Study Group, Bashiri FA, Wood NW, Rothman JE, Alkuraya FS, Houlden H. Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination. Am J Hum Genet. 2017 Jun 1;100(6):969-977.

PubMed ID: 
28575651

Spinocerebellar Ataxia 3

Clinical Characteristics
Ocular Features: 

External ophthalmoplegia in some form is usually present and there may be a supranuclear component.  Smooth horizontal movements are impaired and saccades are dysmetric.  Gaze-evoked nystagmus is a common finding.  The eyes are often described as 'bulging' and this has been attributed to eyelid retraction.  With time the abnormal saccadic movements slow resulting in ophthalmoparesis with restriction of upgaze.

Systemic Features: 

This form of spinocerebellar ataxia is considered to be the most frequent.  It is a progressive disease in all aspects which accounts for some of the considerable clinical heterogeneity reported.  Onset is likewise highly variable depending upon the number of repeats but usually sometime between the second to fifth decades.  In a large cohort of Azorean individuals the mean age of onset was reported to be 37 years.

An unsteady gait, dysarthric speech, general clumsiness, and diplopia are among the early symptoms.  Nystagmus, spasticity, and various autonomic signs including reduced bladder control may also be noted.  Chronic pain, sleep disturbances, impaired mental functioning, and memory deficits are often present and some authors have labelled these as indicative of dementia.

Virtually all clinical signs progress with ambulation difficulties requiring the need for assistive devices about a decade after the onset of disease.  Eventually signs of brain stem involvement appear with facial atrophy, perioral twitching, tongue fasciculations and atrophy, and dysphagia. Some degree of peripheral polyneuropathy with muscle wasting and loss of sensation are often present.  Tremors and other signs of Parkinsonism may be present.  Dystonic movements are often seen.

Imagining of the brain has revealed pontocerebellar atrophy and enlargement of the 4th ventricle but this is variable.  Nerve conduction studies documents involvement of the sensory nerves.  Neuropathologic studies show widespread neuronal loss in the CNS and spinal cord.

Genetics

This is considered to be an autosomal dominant disorder caused by an excess of heterozygous trinucleotide repeats in the ataxin3 gene (14q32) encoding glutamine.  The number in normal individuals is up to 44 repeats whereas patients with SCA3 have 52-86 repeats.  However, clinical signs of SCA3 have been found in patients with as few as 45 glutamine repeats.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Physical and occupational therapy combined with regular exercise has been reported to slow the progression of symptoms.

References
Article Title: 

Machado-Joseph disease

Sudarsky L, Coutinho P. Machado-Joseph disease. Clin Neurosci. 1995;3(1):17-22. Review.

PubMed ID: 
7614089

Neurodevelopmental Disorder with Progressive Microcephaly, Spasticity, and Brain Anomalies

Clinical Characteristics
Ocular Features: 

 Examined patients have optic atrophy with nystagmus and roving eye movements.

Systemic Features: 

There are extensive and, in most cases, progressive CNS abnormalities resulting in severe neurodevelopmental deficits.  Infants at birth have progressive truncal hypotonia and limb spasticity.  Motor deficits result in little spontaneous movement, resulting in poor sucking, and respiratory difficulties.  Language does not develop and there is profound mental retardation. Progressive microcephaly is a characteristic finding.  There are often extrapyramidal signs such as rigidity and dystonic posturing.

Dysmorphic features include a short nose, high-arched palate, low-set and posteriorly rotated ears, micrognathia, postaxial polydactyly, hirsutism, pectus carinatum, contractures of large joints, and hyperextensibility of small joints.

Brain imaging shows a progressive leukoencephalopathy, cerebral and cerebellar atrophy, and delayed myelination.  The corpus callosum is often thin and the ventricles appear enlarged.  The lifespan is generally short with death occurring in infancy or early childhood.

Genetics

This autosomal recessive disorder results from homozygous mutations in the PLAA gene (9p21). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins

Hall EA, Nahorski MS, Murray LM, Shaheen R, Perkins E, Dissanayake KN, Kristaryanto Y, Jones RA, Vogt J, Rivagorda M, Handley MT, Mali GR, Quidwai T, Soares DC, Keighren MA, McKie L, Mort RL, Gammoh N, Garcia-Munoz A, Davey T, Vermeren M, Walsh D, Budd P, Aligianis IA, Faqeih E, Quigley AJ, Jackson IJ, Kulathu Y, Jackson M, Ribchester RR, von Kriegsheim A, Alkuraya FS, Woods CG, Maher ER, Mill P. PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins. Am J Hum Genet. 2017 May 4;100(5):706-724.

PubMed ID: 
28413018

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy

Falik Zaccai TC, Savitzki D, Zivony-Elboum Y, Vilboux T, Fitts EC, Shoval Y, Kalfon L, Samra N, Keren Z, Gross B, Chasnyk N, Straussberg R, Mullikin JC, Teer JK, Geiger D, Kornitzer D, Bitterman-Deutsch O, Samson AO, Wakamiya M, Peterson JW, Kirtley ML, Pinchuk IV, Baze WB, Gahl WA, Kleta R, Anikster Y, Chopra AK. Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy. Brain. 2017 Feb;140(Pt 2):370-386.

PubMed ID: 
28007986

Ataxia with Oculomotor Apraxia 3

Clinical Characteristics
Ocular Features: 

Ocular movement abnormalities are noted at the same time as other peripheral motor difficulties.  Slow saccadic eye movements, and head-eye lag are evident.  Pursuit movements are normal.

Systemic Features: 

Onset of gait instability occurs in the second decade of life with dysmetria and frequent falls. The eye movement abnormalities, dysarthria, and axial dysmetria with distal muscle atrophy and weakness are present at the same time.  Distal sensory deficits with lack of sensory nerve action potentials are also present in the lower limbs.  The upper limbs are involved somewhat later but with less pronounced movement impairment.  Hyporeflexia or areflexia is common.  The disorder is progressive with loss of independent mobility by the third decade.

Brain and spinal cord MRI imaging reveals cerebellar atrophy of the folia and vermis.  Persistently elevated alpha-fetoprotein levels have been found but no hypoalbuminemia.

Genetics

Homozygous missense mutations in the PIK3R5 gene (17p12-p13) have been associated with this clinical picture in one family of 4 affected sibs born of consanguineous parents.

See also Ataxia with Oculomotor Apraxia 1 (208920) with hypoalbuminemia, Ataxia with Oculomotor Apraxia 2 (606002) (also known as Spinocerebellar Ataxia, Autosomal Recessive 1 or SCAR1), and Ataxia with Oculomotor Apraxia 4 (616267).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Kufor-Rakeb Syndrome

Clinical Characteristics
Ocular Features: 

Most patients have a supranuclear gaze paresis.  Patients later may have dystonic oculogyric spasms.

Systemic Features: 

This is a rapidly progressive neurodegenerative disorder with juvenile onset.  First signs of Parkinisonism are evident between the ages of 12 and 16 years of age.  Within a year of onset severe motor handicaps develop along with some degree of dementia with aggression and visual hallucinations.  Cognitive decline is often a feature.  Fine tremors in the chin may be seen along with other extrapyramidal signs but these are not prominent in the limbs.  Instead there is often rigidity and bradykinesia.  Dysphagia, dysarthria, and ataxia are features in many patients.  Peripheral sensory neuropathy and anosmia are present in some individuals. 

Brain imaging often reveals generalized atrophy of the cerebellum, cerebral cortex, and brainstem.

Genetics

This condition results from homozygous or compound heterozygous mutations in the ATP13A2 gene (1p36.13).  

Biallelic mutations in the same gene are also responsible for spastic paraplegia 78 (617225) with somewhat similar clinical features except for the general absence of Parkinsonism.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There may be an initial therapeutic response to L-DOPA but this is often not maintained

References
Article Title: 

Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)

Estrada-Cuzcano A, Martin S, Chamova T, Synofzik M, Timmann D, Holemans T, Andreeva A, Reichbauer J, De Rycke R, Chang DI, van Veen S, Samuel J, Schols L, Poppel T, Mollerup Sorensen D, Asselbergh B, Klein C, Zuchner S, Jordanova A, Vangheluwe P, Tournev I, Schule R. Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78). Brain. 2017 Feb;140(Pt 2):287-305.

PubMed ID: 
28137957

Encephalopathy, Progressive, with Amyotrophy and Optic Atrophy

Clinical Characteristics
Ocular Features: 

Optic atrophy is present.

Systemic Features: 

This is a progressive neurodegenerative condition in which hypotonia and delayed development are evident between birth and 14 months of age.  Developmental milestones, if attained, soon regress accompanied by distal amyotrophy, cognitive impairment that may be severe, ataxia, spastic tetraplegia, dysarthria, and scoliosis.  Seizures often occur.

Brain imaging reveals cerebellar and cerebral atrophy.  Iron accumulation may be seen in the pallidum and substantia nigra.  The corpus callosum appears abnormally thin.  Muscle biopsy shows evidence of denervation atrophy.

Genetics

Homozygous or compound heterozygous mutations in the TBCE gene (1q42.3) can cause this disorder.  

Biallelic mutations in the same gene also cause Kenny-Caffey syndrome type 1 (244460) and a hypoparathyroidism dysmorphism syndrome (241410).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy

Sferra A, Baillat G, Rizza T, Barresi S, Flex E, Tasca G, D'Amico A, Bellacchio E, Ciolfi A, Caputo V, Cecchetti S, Torella A, Zanni G, Diodato D, Piermarini E, Niceta M, Coppola A, Tedeschi E, Martinelli D, Dionisi-Vici C, Nigro V, Dallapiccola B, Compagnucci C, Tartaglia M, Haase G, Bertini E. TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy. Am J Hum Genet. 2016 Oct 6;99(4):974-983.

PubMed ID: 
27666369

Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy

Flex E, Niceta M, Cecchetti S, Thiffault I, Au MG, Capuano A, Piermarini E, Ivanova AA, Francis JW, Chillemi G, Chandramouli B, Carpentieri G, Haaxma CA, Ciolfi A, Pizzi S, Douglas GV, Levine K, Sferra A, Dentici ML, Pfundt RR, Le Pichon JB, Farrow E, Baas F, Piemonte F, Dallapiccola B, Graham JM Jr, Saunders CJ, Bertini E, Kahn RA, Koolen DA, Tartaglia M. Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy. Am J Hum Genet. 2016 Oct 6;99(4):962-973.

PubMed ID: 
27666370

Epileptic Encephalopathy, Early Infantile 48

Clinical Characteristics
Ocular Features: 

Poor eye contact is present from infancy.  Optic atrophy has been reported in several patients and features of retinitis pigmentosa were present in sibs of one family.

Systemic Features: 

Infants usually present with hypotonia and feeding difficulties.  Global developmental delay is also noted early and becomes more obvious with time.  Seizures are often seen early and become intractable.  Many individuals have microcephaly.  Hypermobility with dyskinesias and hyporeflexia are often present.  Speech is generally absent and many individuals are unable to sit or walk.

Brain imaging often shows atrophy of the cerebrum and cerebellum accompanied by enlarged ventricles and a thin corpus callosum.

Genetics

Homozygous or compound heterozygous mutations in the AP3B2 gene (15q25.2) can be responsible for this condition.

For another somewhat similar condition see early onset epileptic encephalopathy 28 (616211) with autosomal recessive inheritance.  For an autosomal dominant condition with a similar clinical picture, see early onset epileptic encephalopathy 47 (617166).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2 Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy

Assoum M, Philippe C, Isidor B, Perrin L, Makrythanasis P, Sondheimer N, Paris C, Douglas J, Lesca G, Antonarakis S, Hamamy H, Jouan T, Duffourd Y, Auvin S, Saunier A, Begtrup A, Nowak C, Chatron N, Ville D, Mireskandari K, Milani P, Jonveaux P, Lemeur G, Milh M, Amamoto M, Kato M, Nakashima M, Miyake N, Matsumoto N, Masri A, Thauvin-Robinet C, Riviere JB, Faivre L, Thevenon J. Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2 Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy. Am J Hum Genet. 2016 Dec 1;99(6):1368-1376.

PubMed ID: 
27889060

Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield

Anazi S, Maddirevula S, Faqeih E, Alsedairy H, Alzahrani F, Shamseldin HE, Patel N, Hashem M, Ibrahim N, Abdulwahab F, Ewida N, Alsaif HS, Al Sharif H, Alamoudi W, Kentab A, Bashiri FA, Alnaser M, AlWadei AH, Alfadhel M, Eyaid W, Hashem A, Al Asmari A, Saleh MM, AlSaman A, Alhasan KA, Alsughayir M, Al Shammari M, Mahmoud A, Al-Hassnan ZN, Al-Husain M, Osama Khalil R, Abd El Meguid N, Masri A, Ali R, Ben-Omran T, El Fishway P, Hashish A, Ercan Sencicek A, State M, Alazami AM, Salih MA, Altassan N, Arold ST, Abouelhoda M, Wakil SM, Monies D, Shaheen R, Alkuraya FS. Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. Mol Psychiatry. 2016 Jul 19. doi: 10.1038/mp.2016.113. [Epub ahead of print].

PubMed ID: 
27431290

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