tremor

Combined Oxidative Phosphorylation Deficiency 32

Clinical Characteristics
Ocular Features: 

Ocular signs are common but variable.  Patients may not make eye contact and sometimes have disconjugate eye movements.  Strabismus (usually exotropia) and nystagmus or often present.

Systemic Features: 

Six patients from 4 unrelated families of mixed ethnic backgrounds have been reported.  Infants within the first 4 to 6 months of life had evidence of developmental delay and neurodevelopmental regression.  Poor feeding and breathing difficulties are often noted in this period.  Other later signs are axial hypotonia, abnormal movements such as tremor, spasticity, hyperkinetic movements, dystonia with eventual regression of milestones.  Joint contractures and kyphoscoliosis may develop. 

Microcephaly was noted in several infants and brain imaging in all patients reveals abnormal T2- weighted signals in the brainstem and specifically in the basal ganglia.  Decreased activity in muscle mitochondrial respiratory complexes I, III, and IV has been documented.  Lactate may be increased in serum and the CSF.  Postmortem studies show brain vascular proliferation and gliosis in basal structures.

Genetics

Homozygous or compound heterozygous mutations in MRPS34 (16p13.3) are the basis for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

Lake NJ, Webb BD, Stroud DA, Richman TR, Ruzzenente B, Compton AG, Mountford HS, Pulman J, Zangarelli C, Rio M, Bodaert N, Assouline Z, Sherpa MD, Schadt EE, Houten SM, Byrnes J, McCormick EM, Zolkipli-Cunningham Z, Haude K, Zhang Z, Retterer K, Bai R, Calvo SE, Mootha VK, Christodoulou J, Rotig A, Filipovska A, Cristian I, Falk MJ, Metodiev MD, Thorburn DR. Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome. Am J Hum Genet. 2017 Aug 3;101(2):239-254.

PubMed ID: 
28777931

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

Spinocerebellar Ataxia 42

Clinical Characteristics
Ocular Features: 

 Saccadic eye movements with nystagmus and diplopia have been reported (7 of 10 reported patients).

Systemic Features: 

Cerebellar signs usually have their onset in midlife or later with slow progression.  Most patients are mildly to moderately disabled.  Dysarthria, dysphagia, and a spastic gait are experienced by the majority of individuals.  Hyperreflexia and a positive Babinski sign are commonly presently.  Mild cognitive impairment and depression have been seen in a minority of patients.

Brain MRIs show cerebellar hemispheric and vermian atrophy.  The cerebral cortex appeared histologically normal in one deceased patient.

Genetics

This disorder is caused by heterozygous mutations in the CACNA1G gene (17q21.33).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Cataracts, Ataxia, Short Stature, and Mental Retardation

Clinical Characteristics
Ocular Features: 

Cataracts are present in both sexes but the opacification is more extensive in males and only partial in females.  The cataracts are congenital in males but apparently develop later in females who complain of blurred vision from early childhood or during teenage years.  The lenses in females have punctate and pulverulent opacities as well as posterior subcapsular sclerosis.  Vision has been estimated as hand motion from early childhood in boys and about 20/40 in females in the first two decades of life.

Systemic Features: 

Males have mild to moderate mental retardation, muscle hypotonia and weakness with postural tremor.  Their standing position is broad-based and they are unable to sit or stand otherwise without some support.  They are usually unable to walk unassisted.  Speech is dysarthric and its development is delayed.  Females are neurologically normal.

Genetics

A locus containing the disease allele at Xpter-q13.1 cosegregates with the cataract phenotype in both sexes.  The gene mutation has not been identified.  This can be called an X-linked recessive disorder with partial expression in heterozygous females.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Cataract surgery may be indicated in young females and may be beneficial in infant boys.

References
Article Title: 

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: 

Gillespie Syndrome

Clinical Characteristics
Ocular Features: 

Bilateral aniridia, partial or complete, is the ocular characteristic of Gillespie syndrome.  The iris may be relatively intact but immobile leading to the description in some patients of "dilated and fixed pupils", or congenital mydriasis.  The pupillary margin may be scalloped with iris strands to the lens.  The pupillary sphincter is sometimes absent and the mesodermal surface missing.  The fovea sometimes appears hypoplastic and some patients have decreased visual acuity.  Strabismus and ptosis are often present.  There may also be retinal hypopigmentation.  Cataract, glaucoma, and corneal opacities are not present. 

Systemic Features: 

Most patients have some degree of developmental delay ranging from difficulties with fine motor tasks to frank mental retardation.  Many have a hand tremor, some degree of hypotonia, and learning difficulties.  MRI imaging often shows cerebellar and sometimes cerebral hypoplasia. 

Genetics

This is an autosomal dominant disorder usually due to a heterozygous mutation in the PAX6 gene (11p13).  However, some patients with typical features do not have a mutation in this gene suggesting that there is genetic heterogeneity.  Some patients without point mutations nevertheless have defects in adjacent DNA suggesting a positional effect.  The possibility of autosomal recessive inheritance in some families with parental consanguinity cannot be ruled out.  The PAX6 gene plays an important role in iris development as it is also mutant in simple aniridia (106210) and in Peters anomaly (604229).

Mutations in the ITPR1 gene have also been identified in Gillespie syndrome.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Pantothenate Kinase-Associated Neurodegeneration

Clinical Characteristics
Ocular Features: 

Clinically evident retinal degeneration is present in a significant number (25-50%) of individuals.  However, when combined with ERG evidence the proportion rises to 68%.  When present it occurs early and one series reported that it is unlikely to appear later if it was not present early in the course of the neurodegeneration.  Some patients have a fleck-like retinopathy.  Optic atrophy may be present in advanced cases.

Systemic Features: 

This is a disorder primarily of the basal ganglia resulting from progressive damage secondary to iron accumulation.  There is an early onset classic form with symptoms of extrapyramidal disease beginning in the first decade of life and rapid progression to loss of ambulation in about 15 years.  Others with atypical disease may not have symptoms until the second or third decades.  Clumsiness, gait disturbance, and difficulty with tasks requiring fine motor coordination are common presenting symptoms.  Motor tics are often seen.  Dysarthria, dystonia, rigidity and corticospinal signs are often present early as well.  Swallowing difficulties may be severe sometimes leading to malnutrition.  Cognitive decline and psychiatric disturbances such as obsessive-compulsive behavior and depression may follow.  Independent ambulation is lost in the majority of patients within one to two decades.    Brain MRIs show an ‘eye of the tiger’ sign with a specific T2- weighted pattern of hyperintensity within the medial globus pallidus and the substantia nigra pars reticulata.

Genetics

Iron accumulation in the basal ganglia resulting from homozygous mutations in the PANK2 gene (20p13-12.3) encoding a pantothenate kinase leads to the classic form of this autosomal recessive disorder. 

This is the most common of several diseases of neurodegeneration with iron accumulation in the brain known collectively as NBIAs.  The group is genetically heterogeneous with many overlapping features.  Mutations in PLA2G6 cause NBIA2A (256600) and NBIA2B (610217) while mutations in a FLT gene cause NBIA3 (606159). The latter does not have apparent eye signs.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Pharmacologic treatment is aimed at alleviation of specific symptoms such as dystonia and spasticity.  Some symptoms may improve with deep brain stimulation.

References
Article Title: 

Optic Atrophy 3 and Cataracts

Clinical Characteristics
Ocular Features: 

There is considerable variation in age of onset and severity of clinical disease.  Cataracts may be evident in the first decade of life but in most cases by the second decade.  They are usually described as anterior or posterior cortical opacities.  Progression of opacification is slow and most patients do not require removal until late adulthood and some never require surgery. Visual impairment from optic atrophy may be evident in infancy and some patients experience a worsening in late adulthood.  Visual acuity is highly variable.  Temporal pallor may be present in childhood or later.

Systemic Features: 

Neurologic signs such as tremor, extrapyramidal rigidity in the upper extremities, and ataxia are seldom present until after the age of 50 years.  However not all patients have neurologic disease.

Genetics

This disorder is inherited in an autosomal dominant pattern as a result of a mutation in the OP3 gene (19q13.2-q13.3) encoding an inner membrane mitochondrial protein.  It is allelic to autosomal recessive optic atrophy-3, or 3-methylglutaconic aciduria type III (258501), sometimes called Behr early onset optic atrophy (210000). 

Optic atrophy 3 is less severe than in Behr optic atrophy and the presence of cataracts is an important distinguishing feature.  For these reasons, optic atrophy 3 is discussed as a separate disorder here.   However, the nosology remains unclear since not all individuals with Behr optic atrophy have 3-methylglutaric acidemia.  

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is available for the optic atrophy.  Cataract surgery may be necessary for visually significant lens opacities.

References
Article Title: 

OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract

Reynier P, Amati-Bonneau P, Verny C, Olichon A, Simard G, Guichet A, Bonnemains C, Malecaze F, Malinge MC, Pelletier JB, Calvas P, Dollfus H, Belenguer P, Malthi?(r)ry Y, Lenaers G, Bonneau D. OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract. J Med Genet. 2004 Sep;41(9):e110.

PubMed ID: 
15342707

[On a heredo-familial disease combining cataract, optic atrophy, extrapyramidal symptoms and certain defects of Friedreich's disease]

GARCIN R, RAVERDY P, DELTHIL S, MAN HX, CHIMENES H. [On a heredo-familial disease combining cataract, optic atrophy, extrapyramidal symptoms and certain defects of Friedreich's disease. (Its nosological position in relation to the Behr's syndrome, the Marinesco-Sjogren syndrome and Friedreich's disease with ocular symptoms.]. Rev Neurol (Paris). 1961 May;104:373-9. French.

PubMed ID: 
13703570

Optic Atrophy 2, X-Linked

Clinical Characteristics
Ocular Features: 

Visual symptoms can begin in early childhood (males only) and vision deteriorates slowly.  All affected individuals have optic atrophy with acuities ranging from 20/30 to 20/100.  ERGs are usually normal whereas VEPs show prolonged latencies.  Color vision is variably defective and central scotomas are present.

Systemic Features: 

Some but not all patients have additional neurological signs including absent ankle jerks, hyperactive knee jerks, extensor plantar reflexes, dysarthria and dysdiadochokinesia.  Symptoms are usually minor.  Obligatory female carriers do not have optic atrophy or neurologic signs.  Mental retardation has been reported in a few patients.

Genetics

This is an X-linked recessive disorder secondary to a mutation in OPA2 (Xp11.4-p11.21). Only males are affected and female carriers are clinically normal.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

No treatment is available for the optic atrophy.

References
Article Title: 
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