ataxia

Marinesco-Sjogren Syndrome

Clinical Characteristics
Ocular Features: 

Congenital cataracts are one of the cardinal features of Marinesco-Sjogren syndrome but lens opacities may have a later onset and may be progressive as well.  Strabismus and nystagmus are sometimes present.

Systemic Features: 

Non-ocular features include cerebellar atrophy, psychomotor developmental delays, mental retardation, and muscle weakness.  Dysarthria is common.  The myopathy has its onset in childhood and is progressive with weakness, hypotonia, and atrophy eventually leading to total disability in some cases.  Progression of motor dysfunction may, however, stabilize in some patients but at an unpredictable level.  Infants are often 'floppy babies'.  MRI studies reveal cerebellar atrophy.  Serum creatine kinase levels are increased and muscle biopsies show chronic myopathic changes.  Skeletal features include short stature, pectus carinatum, and secondary kyphoscoliosis and foot deformities.  Bone abnormalities may be seen in the digits.

Genetics

This is an autosomal recessive condition resulting from mutations in the SIL1 gene (5q31).  It is sometimes confused with the condition known as congenital cataracts, facial dysmorphism, and neuropathy (604168) with which it shares some clinical features.  The two conditions are genetically distinct since they are caused by mutations in different genes.

See also Muscular Dystrophy, Congenital Cataracts, with Cataracts and Intellectual Disability for a similar disorder caused by a different mutation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Visually significant cataracts may need to be removed in the first decade of life.  Skeletal deformities may benefit from surgery and hormone therapy should be considered in specific cases.

References
Article Title: 

The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone

Anttonen AK, Mahjneh I, Hamalainen RH, Lagier-Tourenne C, Kopra O, Waris L, Anttonen M, Joensuu T, Kalimo H, Paetau A, Tranebjaerg L, Chaigne D, Koenig M, Eeg-Olofsson O, Udd B, Somer M, Somer H, Lehesjoki AE. The gene disrupted in Marinesco-Sjogren syndrome encodes SIL1, an HSPA5 cochaperone. Nat Genet. 2005 Dec;37(12):1309-11.

PubMed ID: 
16282978

Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome

Lagier-Tourenne C, Chaigne D, Gong J, Flori J, Mohr M, Ruh D, Christmann D, Flament J, Mandel JL, Koenig M, Dollfus H. Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome. J Med Genet. 2002 Nov;39(11):838-43.

PubMed ID: 
12414825

Cataracts, Congenital, Facial Dysmorphism, and Neuropathy

Clinical Characteristics
Ocular Features: 

Cataracts, microphthalmia, and microcornea (mean diameter ~7.5 mm) are present at birth and precede the onset of neurological symptoms.  The lens opacities often consist of anterior and posterior subcapsular opacities but the entire lens may be opaque as well.  Some adults have bilateral ptosis.  The pupils are often small and have sluggish responses to light and mydriatics.  Strabismus and horizontal pendular nystagmus are common.  Visual impairment may be severe.

Systemic Features: 

The neuropathy is primarily motor and usually begins in the lower extremities but is progressive and eventually involves the arms as well.  Motor development is slow and walking is often unsteady from the start.  Speaking may not have its onset until 3 years of age.   Mild, nonprogresssive cognitive defects and mental retardation are often present.  Sensory neuropathy with numbness and tingling develops in the second decade.  Mild chorea, upper limb tremor, mild ataxia, and extensor plantar responses may be seen.  Deafness has been described.  Nerve conduction studies and biopsies have documented a demyelinating polyneuropathy while MRIs demonstrate cerebral and spinal cord atrophy which may be seen in the first decade of life.  The MRI in many patients reveals diffuse cerebral atrophy, enlargement of the lateral ventricles and focal lesions in subcortical white matter.  Most individuals have mild cognitive deficits while psychometric testing reveals borderline intelligence in a minority.

Patients are susceptible to acute rhabdomyolysis following viral infections.  Most are severely disabled by the third decade.

The facial dysmorphism appears in childhood and consists of a prominent midface, hypognathism, protruding teeth, and thickening of the lips.  Spinal deformities occur in the majority of individuals along with foot and hand claw deformities.  All patients are short in stature.  Hypogonadotropic hypogonadism is a common feature and females may be infertile.  Amenorrhea is often present by the age of 25-35 years.

Genetics

This is an autosomal recessive disorder found primarily among European Gypsies.  It is caused by mutations in the CTDP1 gene (18q23-qter).  It is sometimes confused with Marinesco-Sjogren syndrome (248800) with which it shares some clinical features but the two are genetically distinct.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts often require removal in the first decade of life. Scoliosis and foot deformities may benefit from surgical correction.  Supportive care and physical therapy can be helpful.

References
Article Title: 

Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome

Lagier-Tourenne C, Chaigne D, Gong J, Flori J, Mohr M, Ruh D, Christmann D, Flament J, Mandel JL, Koenig M, Dollfus H. Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome. J Med Genet. 2002 Nov;39(11):838-43.

PubMed ID: 
12414825

Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations

Tournev I, Kalaydjieva L, Youl B, Ishpekova B, Guergueltcheva V, Kamenov O, Katzarova M, Kamenov Z, Raicheva-Terzieva M, King RH, Romanski K, Petkov R, Schmarov A, Dimitrova G, Popova N, Uzunova M, Milanov S, Petrova J, Petkov Y, Kolarov G, Aneva L, Radeva O, Thomas PK. Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations. Ann Neurol. 1999 Jun;45(6):742-50.

PubMed ID: 
10360766

Spastic Ataxia 7, with Miosis

Clinical Characteristics
Ocular Features: 

Several large pedigrees have been reported in which both males and females had congenital miosis and decreased pupillary light responses.  The pupils are about 2 mm in size and have been described as 'fixed' since they do not dilate in low light or constrict in bright light.  They also do not respond well to mydriatics.  Several individuals also had nystagmus and dysconjugate eye movements.

Optic atrophy is not a consistent feature although several in the original reported family were reported to have this feature which is often found in other spastic ataxia disorders, such as Friedreich's ataxia (229300).

Systemic Features: 

Ataxia in gait and limb motion with pyramidal signs is part of this disorder.  Deep tendon reflexes are increased and plantar responses are often extensor in direction.  Both pyramidal signs and the ataxia progress little.  Affected individuals begin walking late and often have slurred speech.  The IQ's in one family were measured to be less than 90.  CT scans have not revealed cerebellar atrophy.

Genetics

This condition is likely inherited in an autosomal dominant pattern based on one pedigree with 21 members in 4 generations and another with an affected mother and 3 of 5 affected children.  Nothing is known about the locus responsible.

Optic atrophy is also found in autosomal recessive SPAX4 (613672) and in an ill-defined autosomal recessive form of spastic ataxia with mental retardation (270500).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for this disorder.

References
Article Title: 

Cerebrotendinous Xanthomatosis

Clinical Characteristics
Ocular Features: 

Juvenile cataracts are the primary ocular feature of this disorder and are found in virtually all patients.  These often cause the first symptoms and become evident in the first decade and almost always by the third decade of life.  Lens opacification may require extraction at that time and aspirated lens material may contain lipid-containing vacuoles.  However, some cataracts may not be diagnosed until the 5th or 6th decades after the onset of neurological symptoms, usually because the opacities are located in the peripheral cortex and do not cause visual symptoms. 

Optic atrophy occurs in nearly half of affected individuals.  Yellowish flakes resembling cholesterol crystals can sometimes be seen in the vitreous. The fundus may have scattered hard exudates and cholesterol-like deposits along the vascular arcades and arterioles show evidence of atherosclerosis.  RPE window defects are common.

Systemic Features: 

CTX has serious systemic neurologic signs and symptoms resulting from a deficiency of a mitochondrial enzyme, sterol 27-hydroxylase.  The result is reduced bile acid synthesis and increased levels of cholestanol in plasma, tissues, and CSF.  This results in a characteristic phenotype of tendon xanthomas, and neurological dysfunction including mental regression or illness, cerebellar ataxia, peripheral neuropathy, seizures, and pyramidal signs to various degrees.  Neonatal jaundice and diarrhea are common.

Genetics

This autosomal recessive disorder results from a mutation in the CYP27A1 gene (2q33-qter) encoding sterol 27-hydroxylase.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

This is a treatable disorder in which administration of chenodeoxycholic acid (CDCA) is beneficial.  This compound is virtually absent from bile in people with CTX.  Exogenous administration reduces high levels of cholesterol and cholestanol in the CSF, tissues, and plasma with improvement in mental function and signs of peripheral neuropathy and cerebellar dysfunction.  It is frequently given in combination with other HMG-CoA inhibitors such as pravastatin.  Early diagnosis and treatment are important.

References
Article Title: 

Kearns-Sayre Syndrome

Clinical Characteristics
Ocular Features: 

Ptosis and progressive ophthalmoplegia usually have their onset before the second decade of life.  Pigmentary retinopathy is common with a variable clinical pattern of simple salt-and-pepper pigmentation or pigmentary clumping resembling retinitis pigmentosa.

Systemic Features: 

Atrioventricular conduction defects including complete heart block, cardiomyopathy, short stature, elevated CSF protein, and ataxia are among the most frequent extraocular features seen.  Pharyngeal, facial, and skeletal muscle weakness seem to be common features.  Growth retardation, delayed sexual maturation, and mental deterioration occur in some patients. Older patients have a sensorineural hearing deficit as well.

EEG abnormalities are often present.  CT scans reveals a diffuse leukoencephalopathy as well as a variety of CNS abnormalities in the cerebellum and brain stem.  Muscle biopsies reveal 'ragged red' fibers.

This is a progressive disorder and many patients die in the third or fourth decades of life.

Genetics

Unlike many syndromes of external ophthalmoplegia with deletions in mitochondria, no nuclear DNA mutations have been associated with this disorder.  However, it is a clinically and genetically heterogeneous condition.  Exclusively maternal transmission consistent with mitochondrial disease has been observed in some familial cases.  Other familial cases suggest autosomal inheritance and in some the transmission pattern is consistent with autosomal recessive inheritance.  Many if not most cases occur sporadically.

Mitochondrial DNA defects in muscle and brain vary in size and location and even the proportion of normal to abnormal mitochondria among cells varies. This may account for some of the clinical heterogeneity.

Treatment
Treatment Options: 

Coenzyme Q(10) may decrease fatigue with improvement in eye muscle movement and a lessening in the degree of heart block.  Pacemakers may be necessary in some patients.  Exercise is recommended for patients with significant skeletal myopathy.

References
Article Title: 

External Ophthalmoplegia, POLG and mtDNA Mutations

Clinical Characteristics
Ocular Features: 

Progressive external ophthalmoplegia of these types is often associated with widespread neurological and muscle manifestations.  The ophthalmoplegia is adult in onset and frequently combined with exercise intolerance.  Significant lens opacities may be seen in early childhood but may not cause vision problems until early adulthood. Progressive ptosis is often an early and disabling sign.

Systemic Features: 

Facial muscles can be weak, generally in older individuals.  Some patients complain of dysphagia.  Sensoirneural hearing loss, dysarthria, and dysphonia are often associated.  Neurological symptoms include ataxia, sensory neuropathy, tremors, depression and symptoms of parkinsonism but these are variable.   Some patients experience rhabdomyolysis following alcohol consumption.  Dilated cardiomyopathy can be a part of the autosomal recessive form of this disease.

A possible subcategory of this disease is associated with hypogonadism evidenced by delayed sexual maturation, primary amenorrhea, early menopause and testicular atrophy.  Other features as described above may be associated.  Muscle biopsy shows ragged-red fibers with multiple mitochondrial deletions.

Genetics

Progressive external ophthalmoplegia of the type described here is the result of mutations in the autosomal gene POLG combined with deletions in mitochondrial DNA.  POLG mutations account for 13-45% of patients with progressive external ophthalmoplegia who also have mitochondrial deletions.  The inheritance pattern in some families resembles the classical autosomal dominant pattern (PEOA1, 157640) whereas in others the pattern suggests autosomal recessive transmission (PEOB, 258450).  The autosomal defect is in the POLG gene at locus 15q25 which codes for the nuclear-encoded DNA polymerase-gamma gene.  The phenotype in the recessive disease tends to be more severe than in autosomal dominant cases. 

Other autosomal mutations with a less complex clinical picture associated with ophthalmoplegia are located in genes ANT1 (SLC25A4) (609283) at 4q35, and C10ORF2 (606075) at 10q24.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available for the general disorder but consideration should be given to ptosis repair.

References
Article Title: 

Sulfite Oxidase Deficiency

Clinical Characteristics
Ocular Features: 

Dislocated lenses are the only significant ocular features of this disorder.  In one patient the lenses were said to be in normal position at 5.5 months of age but mild nasal subluxation of both lenses was present at 11 months.  In a series of 22 patients, 10 had dislocated lenses and one had spherophakia.  Lens dislocations occur early and maybe even congenitally in some cases as the diagnosis has been made in seven children before one year of age.  On the other hand it is not a consistent sign since the lenses were not dislocated in seven individuals who were examined specifically for this sign.

Systemic Features: 

Outside of the eye, the main features of this disorder are secondary to neurological damage.  Symptoms of irritability, poor feeding, ataxia, and language development may be seen in the first year or two of life.  Respiratory distress can be a feature in neonates.  Hypotonia, dystonia and choreoathetosis may be seen as well.  Seizures (sometimes with opisthotonus) often occur in the first days or weeks of life.  Later, generalized hypertonia and hyperactive reflexes are present.  Global developmental delays occur in nearly 80% of patients.  However, some patients also have a later onset with a milder course indicating that the full range of clinical expression remains to be determined.

Genetics

A number of mutations in the SUOX gene on chromosome 12 (12q13.13) cause this rare autosomal recessive disorder.  Less than 50 cases have been reported worldwide.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Not enough patients have been evaluated for long enough to determine the optimum treatment but low protein diets and restriction of sulfur containing amino acids have been tried with mixed results.

References
Article Title: 

Isolated sulfite oxidase deficiency

Claerhout H, Witters P, Regal L, Jansen K, Van Hoestenberghe MR, Breckpot J, Vermeersch P. Isolated sulfite oxidase deficiency. J Inherit Metab Dis. 2017 Oct 4. doi: 10.1007/s10545-017-0089-4. [Epub ahead of print].

PubMed ID: 
28980090

Abetalipoproteinemia

Clinical Characteristics
Ocular Features: 

The major ocular manifestations of abetalipoproteinemia are in the retina which develops diffuse and sometimes patchy pigmentary changes often called atypical retinitis pigmentosa.  In other cases the picture resembles retinitis punctata albescens with perivascular white spots in the peripheral retina.  Night blindness is an early and prominent symptom with abnormal dark adaptation thresholds evident before fundus pigment changes are seen.  The ERG shows loss of rod function before that of cone function.  The macula may or may not be affected while peripheral fields are often severely constricted.  Loss of photoreceptors occurs throughout life and visual fields show progressive constriction, sometimes with central sparing.  A single case of bilateral disc swelling in a 9 year-old girl has been reported.

Systemic Features: 

Celiac disease and steatorrhea due to a deficiency of circulating chylomicra underlie the malabsorption of vitamins A and E which is probably responsible for the majority of systemic manifestations.  Red blood cells have a peculiar burr-like morphology that has led to the designation 'acanthocytes'.  Liver failure and cirrhosis sometimes occur.  Plasma lipids are generally low including cholesterol, triglycerides, and beta lipoproteins.  Central and peripheral nerve demyelination occurs leading to a progressive ataxia and other neurological symptoms.

Genetics

This autosomal recessive disease seems to result from an inability to synthesize the apoB peptide that is a part of the LDL and VLDL.   A mutation in the MTP gene (4q22-q24) is responsible.  The gene is sometimes called MTTP as it codes for micosomal triglyceride transfer protein.

Acanthocytosis is also a feature in the autosomal recessive condition known as chorea-acanthocytosis (200150), a progressive degenerative movement disorder primarily affecting the limbs resulting from mutations in the VPS13A gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment with vitamins A and E may be beneficial.  Cone function improves before rod function with massive doses of vitamin A but usually only after months of treatment.  It has been reported that Vitamin A alone without vitamin E is insufficient to arrest the retinal disease.

References
Article Title: 

Behr Early Onset Optic Atrophy Syndromes

Clinical Characteristics
Ocular Features: 

Optic atrophy is the earliest sign in Behr syndrome and may be evident in early childhood.  Nystagmus is a variable feature.  Acuity in the first decade is in the 20/70 to 20/100 range with little worsening in patients followed for a decade or more even though the disc pallor may increase with loss of papillary vasculature.  ERGs are normal but VEPs are usually abnormal.

Systemic Features: 

The nosology of infantile optic atrophy is unclear.   There is no doubt that some familial cases with likely autosomal recessive inheritance lacked (or were not tested for) urinary metabolites considered diagnostic for an optic atrophy disorder with 3-methylglutaconate aciduria (258501) and labeled methylglutaconic aciduria type III (and sometimes Costeff optic atrophy syndrome).  Excretion of 3-methylglutaric acid may also be increased.  But it is also possible that another form of infantile optic atrophy without aminoaciduria also exists.  Early onset (early childhood) optic atrophy, with later (second decade) spasticity, ataxia, extrapyramidal signs and cognitive defects to some degree are common to both.  Dementia, posterior column signs and peripheral neuropathy are more variable clinical signs.  Nerve biopsies and postmortem studies show widespread disease with evidence of chronic neuropathy, neuronal loss, and gliosis.  In Behr's report, the neurologic symptoms remained static after a period of progression.   Others have reported progression with the majority of patients severely handicapped by the third decade of life.

Genetics

Sibs born to consanguineous parents suggest autosomal recessive inheritance in both Behr syndrome with ataxia and in 3-methylglutaconic aciduria, type III.  The latter is most commonly found among Iraqi Jews and is the result of a mutation in the OPA3 gene (19q13.2-q13.3).  The genetic basis for simple Behr infantile optic atrophy is unclear and it is likely that multiple unique entities exist.  This disorder is allelic to an autosomal dominant disorder called Optic Atrophy 3 and Cataracts (165300) but the uniqueness of the latter entity is uncertain.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None known

References
Article Title: 

Ataxia-Telangiectasia

Clinical Characteristics
Ocular Features: 

The ocular manifestations are striking although of little clinical consequence.  The conjunctivae have prominent telangiectases which usually develop between 3 and 5 years of age.  These apparently do not occur intraocularly.    Oculomotor apraxia is often an earlier sign consisting of difficulty in initiation of smooth pursuit movements which patients may modify by head motion in the direction of attempted gaze.  This aspect can be helpful in diagnosis of AT in young children with cerebellar ataxia. 

Systemic Features: 

Telangiectases are often found in the pinnae, on the cheeks, and on the forearms, usually after the onset of neurological signs.  However, this is also a disorder with multiple systemic signs, the most serious of which are unusual sensitivity to ionizing radiation, excessive chromosomal breakage, a deficiency in the immune system, mild cognitive impairment, and increased risk of malignancies.  Lymphomas, often of B-cell origin, and leukemia, usually of T-cell origin, are the most common malignancies but there is a significantly increased risk of breast cancer as well. Serum IgG2 and IgA levels are often reduced and sinopulmonary infections are common.  Serum alpha-fetoprotein levels are usually increased.  The ataxia is progressive and often begins as truncal unsteadiness with limbs involved later.  It is often accompanied by choreoathetosis and/or dystonia which may result in severe disability by the second decade.  Life span is shortened and many patients succumb to their disease by the 3rd and 4th decades. 

In some famiies with confirmed mutations in ATM the disorder presents with signs of primary torsion dystonia and myoclonus-dystonia.  These signs may resemble an apparent autosomal dominant pattern with parent-child transmission.  It is unclear whether these families represent a variant of AT or a unique disorder.  The latter is suggested by an earlier onset of signs, the lack of cerebellar atrophy,  and the absence of ataxia and ocular telangiectases on initial presentation.  The risk of malignancies in these famiies is high.

Some of these signs have been reported in milder form among heterozygous carriers as well.  The most serious is an increased risk of malignancy, perhaps as much as 6.1 times that of non-carriers.  This combined with the inherent sensitivity to ionizing radiation has led to the suggestion that X-rays should be used with caution, especially when considering mammograms among female relatives.

 

Genetics

This is an autosomal recessive disorder as a result of mutations in the ATM gene located at 11q22-q23.  Affected offspring of consanguineous matings are often homozygous for this mutation whereas those from unrelated parents are usually compound heterozygotes.  There is some evidence of genetic heterogeneity based on both clinical and DNA studies (AT variants).

Other conditions with oculomotor apraxia are: ataxia with oculomotor apraxia 1 (208920), ataxia with oculomotor apraxia 2 (602600), and Cogan type oculomotor apraxia (257550) which lacks other neurologic signs. Oculomotor apraxia may be the presenting sign in Gaucher disease (230800, 230900, 231000).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known for the neurologic manifestations.  However, patients and first degree relatives should be monitored for malignancies.  Childhood vaccinations may lead to widespread viral dissemination as a consequence of the immune defect.

References
Article Title: 

Ataxia telangiectasia: a review

Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. Orphanet J Rare Dis. 2016 Nov 25;11(1):159. Review.

PubMed ID: 
27884168

Cognitive Phenotype in Ataxia-Telangiectasia

Hoche F, Frankenberg E, Rambow J, Theis M, Harding JA, Qirshi M, Seidel K, Barbosa-Sicard E, Porto L, Schmahmann JD, Kieslich M. Cognitive Phenotype in Ataxia-Telangiectasia. Pediatr Neurol. 2014 May 5.

PubMed ID: 
25037873

Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites

Saunders-Pullman R, Raymond D, Stoessl AJ, Hobson D, Nakamura T, Pullman S, Lefton D, Okun MS, Uitti R, Sachdev R, Stanley K, San Luciano M, Hagenah J, Gatti R, Ozelius LJ, Bressman SB. Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites. Neurology. 2012 Feb 15. [Epub ahead of print] PubMed PMID: 22345219.

PubMed ID: 
22345219

Pages

Subscribe to RSS - ataxia