athetosis

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

Infantile Cerebellar-Retinal Degeneration

Clinical Characteristics
Ocular Features: 

Visual tracking can be normal during the newborn period but lack of visual fixation and attention soon become evident.  Strabismus, nystagmus, and abnormal pursuit movements are often present.  Optic atrophy has been reported as early as 3 years of age.  VEP and ERG responses are extinguished in the first two years. The nystagmus may be multidirectional.  Acuity loss seems to be progressive.  A progressive retinal degeneration (not further characterized) has been reported.

Systemic Features: 

Infants generally appear normal at birth.  Within the first 6 months they show signs of developmental delay and neurological signs such as truncal hypotonia, seizures, athetosis and head bobbing.  Milestones of sitting, rolling over, and reactions to others are seldom achieved.  Cerebellar brain imaging shows progressive atrophy in all patients and some have cortical atrophy as well.  Some patients have evidence of hearing loss.   Severe failure to thrive and psychomotor delays are usually present.  Death may occur within several months of birth although some live for several decades.

Genetics

This condition results from homozygous or compound heterozygous mutations in the ACO2 gene (22q13.2).  The mutation has also been associated with optic atrophy 9 (616289).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment beyond supportive care is known.

References
Article Title: 

Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy

Metodiev MD, Gerber S, Hubert L, Delahodde A, Chretien D, Gerard X, Amati-Bonneau P, Giacomotto MC, Boddaert N, Kaminska A, Desguerre I, Amiel J, Rio M, Kaplan J, Munnich A, Rotig A, Rozet JM, Besmond C. Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy. J Med Genet. 2014 Dec;51(12):834-8.

PubMed ID: 
25351951

Neurodegeneration with Brain Iron Accumulation

Clinical Characteristics
Ocular Features: 

Optic atrophy is a major ocular feature and the primary cause of visual impairment.  A minority (25%) of patients also have a diffuse fleck retinopathy with a bull’s eye maculopathy.  Later the retinopathy may resemble retinitis pigmentosa with a bone spicule pattern. Nystagmus is often present.  These signs usually follow systemic signs such as difficulties in locomotion.  An apraxia of eyelid opening has been noted and some patients have blepharospasm. 

Systemic Features: 

This is a progressive disorder of the basal ganglia with prominent symptoms of extrapyramidal dysfunction.  Onset is in early childhood or in the neonatal period with delayed development and sometimes mental retardation.  Choreoathetoid writhing movements, stuttering, dysphagia, muscle rigidity, and intermittent dystonia are prominent features.  Seizures are uncommon.  Older individuals may exhibit dementia and ambulation is eventually impaired.  The MRI usually shows an area of hyperintensity in the medial globus pallidus that has been called the ‘eye of the tiger’ sign but this is not pathognomonic.  Axonal degeneration with accumulation of spheroidal inclusions can be seen histologically. 

Genetics

The title of this disorder ‘neurodegeneration with brain iron accumulation’ actually refers to a group of disorders with somewhat common characteristics.  Pentothenate kinase-associated neurodegeneration or NB1A1 (234200) is  the most common of these. 

Types  NBIA2A (256600) and NBIA2B (610217) are caused by mutations in the PLA2G6 gene (22q13.1).  The former can be seen neonatally but usually has its onset in the first two years of life and is sometimes called infantile neuroaxonal dystrophy or Seitelberger disease.  Death may occur before the age of 10 years.  Signs of motor neuron and cerebellar disease are more prominent than in NB1A1. 

NBIA2B has a later onset (4-5 years) and profound sensorimotor impairment but there are many overlapping features and the nosology is confusing.  Mutations in the FTL gene cause yet another form designated NBIA3 (606159) but ocular signs seem to be absent. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is evidence that treatment with deferiprone reduces the amount of iron accumulation in the globus pallidus with motor improvement in at least some patients.  Most patients require supportive care.

References
Article Title: 

Oculocerebral Syndrome with Hypopigmentation

Clinical Characteristics
Ocular Features: 

Patients have severe ocular malformations which so far lack full characterization.  Nearly complete scleralization of the cornea prevents internal evaluation in most cases.  There may be extensive neovascularization of corneal clouding.  Anterior synechiae and cataracts have been described.  Other patients presumed to have the same disorder have normal fundi or diffuse pigmentary changes.  No limbal landmarks can be seen.  The central cornea can be more transparent but no iris can be visualized.  The eyes are microphthalmic as well.  Slow, wandering eye movements are constant.  Spastic ectropion of the lower lids is present. Lashes and eyebrows have minimal pigmentation and like the scalp hair have a slight yellowish tinge.  There is no response to bright light in severe cases whereas in other more mildly affected individuals presumed to have this disorder there is only hypoplasia of the fovea with diffuse retinal pigmentary changes.

Systemic Features: 

Individuals have severe mental retardation from birth and never respond to environmental cues beyond having a marked startle response to auditory stimuli.  Grasp and sucking responses persist at least into the second decade.  The developmental delay persists from birth and patients never achieve normal milestones.  Athetoid, writhing movements are prominent.  The limbs are spastic, and deep tendon reflexes are hyperactive. Contractures are common.  Hypodontia, diastema, and gingival hyperplasia are usually present and the hard palate is highly arched.  The skin is hypopigmented but pigmented nevi may be present and the distribution of melanocytes is uneven microscopically. Cerebellar hypoplasia has been reported in some patients.

Genetics

This is a presumed autosomal recessive disorder based on its familial occurrence and parental consanguinity in some families.  An interstitial deletion [del(3)(q27.1-1q29)] has been identified in the paternal chromosome of a 4-year-old female but the molecular defect remains unknown. 

Clinically heterogeneous cases from Africa, Germany, Italy, Great Britain, and Belgium may not all have the same disorder and evidence for a distinctive phenotype remains elusive.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None available

References
Article Title: 

Oculocerebral syndrome with hypopigmentation (Cross

De Jong G, Fryns JP. Oculocerebral syndrome with hypopigmentation (Cross syndrome): the mixed pattern of hair pigmentation as an important diagnostic sign. Genet Couns. 1991;2(3):151-5.

PubMed ID: 
1801851
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