spasticity

Cataracts, Congenital, and Hypomyelinating Leukodystrophy

Clinical Characteristics
Ocular Features: 

Bilateral cataracts may be present at birth or later in the first decade of life.  The ERG and flash VEPs are normal.

Systemic Features: 

Psychomotor development is initially normal but signs of delay are usually present during the first year of life.  Patients may be able to walk but only with support.  Pyramidal and cerebellar dysfunction, muscle weakness and wasting, dysarthria, truncal hypotonia, intention tremor, and spasticity are evident during the first decade.  Some have seizures.  Cognitive impairment ranges from mild to moderate.  Most patients become wheelchair-bound late in the first decade of life and some do not survive beyond childhood.

Hypomyelination and mild axonal loss may be seen in peripheral nerve biopsies while neuroimaging shows evidence of diffuse and progressive cerebral white matter atrophy.

Genetics

This is an autosomal recessive disorder caused by homozygous mutations in FAM126A (7p15.3) leading to a deficiency of the neuronal protein hyccin.  The result is deficient myelination in both central and peripheral nervous systems.  No symptoms are evident in heterozygotes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The cataracts may be surgically removed.  There is no known treatment for the progressive neurologic deterioration but physical therapy and special education may be helpful.

References
Article Title: 

Novel FAM126A mutations in Hypomyelination and Congenital Cataract disease

Traverso M, Assereto S, Gazzerro E, Savasta S, Abdalla EM, Rossi A, Baldassari S, Fruscione F, Ruffinazzi G, Fassad MR, El Beheiry A, Minetti C, Zara F, Biancheri R. Novel FAM126A mutations in Hypomyelination and Congenital Cataract disease. Biochem Biophys Res Commun. 2013 Aug 30. [Epub ahead of print] PubMed PMID: 23998934.

PubMed ID: 
23998934

Phenotypic characterization of hypomyelination and congenital cataract

Biancheri R, Zara F, Bruno C, Rossi A, Bordo L, Gazzerro E, Sotgia F, Pedemonte M, Scapolan S, Bado M, Uziel G, Bugiani M, Lamba LD, Costa V, Schenone A, Rozemuller AJ, Tortori-Donati P, Lisanti MP, van der Knaap MS, Minetti C. Phenotypic characterization of hypomyelination and congenital cataract. Ann Neurol. 2007 Aug;62(2):121-7.

PubMed ID: 
17683097

Chorioretinopathy with Microcephaly 1

Clinical Characteristics
Ocular Features: 

The ocular features have not been well described.  Small corneas, hyperopia, pale optic nerves and a variety of pigmentary changes in the retina have been reported.  The latter may consist of diffuse, fine or granular pigmentary changes.  Areas of pigmentary atrophy are often associated with patchy areas of pigmentary clumping.  These changes are usually located posterior to the equator.  Choroidal vessels may be sparse where the RPE is absent.  It has been suggested that the patchy pattern of retinal pigmentation resembles ocular toxoplasmosis.  Strabismus is common.  One report suggests microphthalmos in a patient.  Vision has been reported as subnormal from the first year of life but no quantitative data are available.

Systemic Features: 

Microcephaly is a consistent feature.  The forehead is steeply sloped but facial size appears normal.  The palate is highly arched.  Patients often have hyperactive deep tendon reflexes and walk with a shuffling gait.  Children are often hyperactive and highly social.  Intelligence quotients are usually subnormal. No lymphedema has been reported.  At least some patients have cutis marmorata.

On MRI diffuse pachygryria is seen.  The vermis is hypoplastic and the surface area of the corpus callosum is reduced to half of normal. 

Genetics

 Parental consanguinity was present in two reported families and pedigrees are consistent with autosomal recessive inheritance with homozygous mutations of TUBGCP6 (22p22) responsible.

This presumed recessive disorder appears to be different than the autosomal dominant disorder of lymphedema, microcephaly, and chorioretinal dysplasia  (MCLMR) (152950) although molecular confirmation is lacking.

For somewhat similar disorder see Chorioretinopathy with Microcephaly 2 (616171).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is supportive.

References
Article Title: 

Genetic mapping and exome sequencing identify variants associated with five novel diseases

Puffenberger EG, Jinks RN, Sougnez C, Cibulskis K, Willert RA, Achilly NP, Cassidy RP, Fiorentini CJ, Heiken KF, Lawrence JJ, Mahoney MH, Miller CJ, Nair DT, Politi KA, Worcester KN, Setton RA, Dipiazza R, Sherman EA, Eastman JT, Francklyn C, Robey-Bond S, Rider NL, Gabriel S, Morton DH, Strauss KA. Genetic mapping and exome sequencing identify variants associated with five novel diseases. PLoS One. 2012;7(1):e28936. Epub 2012 Jan 17. PubMed PMID: 22279524.

PubMed ID: 
22279524

RAB18 Deficiency

Clinical Characteristics
Ocular Features: 

Microphthalmia with microcornea, lens opacities, small and unresponsive pupils, and optic atrophy are the outstanding ocular features of this syndrome.  The eyes appear deeply set.  Some but not all have ERG evidence of rod and cone dysfunction.  The VEP is usually abnormal.  Short palpebral fissures have been described. 

Systemic Features: 

Patients with the micro syndrome have many somatic and neurologic abnormalities.  Infants usually have feeding problems that is sometimes accompanied by gastroesophageal reflux.  Some degree of psychomotor retardation and developmental delays is common.  Both spasticity and hypotonia have been described.  Some patients have seizures.  Facial hypertrichosis, anteverted ears, and a broad nasal bridge are often noted.   There may be absence of the corpus callosum while diffuse cortical and subcortical atrophy, microgyria, and pachygyria may be evident on MRI imaging.  Hypogenitalism may be a feature in both sexes.  Males may also have cryptorchidism and a micropenis while females can have hypoplasia of the labia minora and clitoris and a small introitus.  Microcephaly is inconsistently present. 

Genetics

This is a clinically and genetically heterogeneous disorder caused by homozygous mutations in at least 4 genes: RAB3GAP1 (WARBM1), RAB3GAP2 (WARBM2), RAB18 (WARBM3), and TBC1D20 (WARBM4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available.  Vision remains subnormal even after cataracts are removed.  Nutrition may be improved with placement of a gastrostomy tube.

References
Article Title: 

New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish

Morris-Rosendahl DJ, Segel R, Born AP, Conrad C, Loeys B, Brooks SS, M?oller L,Zeschnigk C, Botti C, Rabinowitz R, Uyanik G, Crocq MA, Kraus U, Degen I, Faes F. New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish. Eur J Hum Genet. 2010 Oct;18(10):1100-6.

PubMed ID: 
20512159

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: 

Pelizeaus-Merzbacher Disease

Clinical Characteristics
Ocular Features: 

Nystagmus is the major ocular feature in this disease and may appear as early as the first weeks of life in severe cases.  However, more mildly affected individuals may never have nystagmus and, further, it can disappear later.  The ocular movements are usually pendular but may have horizontal and rotatory components as well.  The presence of nystagmus is diagnostically important as it is an uncommon finding in other leukodystrophies.

Systemic Features: 

The classic disease is infantile in onset with hypotonia, titubation, weakness, stridor, respiratory problems, and even seizures often noted in the first weeks of life.   Ataxia, spasticity and cognitive delay are soon apparent.  Infants affected early and severely may never achieve normal motor or mental milestones whereas those less severely affected may at some point ambulate and acquire some language skills.  However, acquired skills may be lost by adolescence.  Survival to the sixth decade of life is common but those with the most severe form of disease may not live beyond the second decade. 

This is an X-linked recessive disorder in which only males have the complete syndrome.  However, multiple carrier females have been studied and many have subtle evidence of disease mainly in gait and motor control.

Genetics

Pelizeaus-Merzbacher disease is the result of mutations in an X-linked gene PLP1 (Xq22).  It is inherited in an X-linked recessive pattern.  Duplication of the PLP1 gene is more common than point mutations.  The signs and symptoms are not diagnostic of PMD as mutations in other genes can cause a similar phenotype. 

Spastic paraplegia-2 (SPG2; 312920)is an allelic disorder in which nystagmus and optic atrophy are also found in some patients.

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

There is no effective treatment for this disease.  Airway protection and seizure control should be applied in specific situations.  Patients often need a feeding tube for adequate nutrition.

References
Article Title: 

Sjogren-Larsson Syndrome

Clinical Characteristics
Ocular Features: 

The retina often has glistening white intraretinal dots which may be concentrated in the macula.  They have been found in 1 to 2 year old infants.  The macula may have ‘punched out’ lesions.  A pigmentary retinopathy is present in about 50% of patients and fluorescein angiography reveals a mottled hyperfluorescence. The cornea often has grayish stromal opacities that become vascularized, most commonly in the lower half.  Most patients have punctate keratitis resulting in marked photophobia.  Visual acuities can range from about 20/40 to finger counting.  The retinal changes may be progressive but EOG and ERG studies do not reveal abnormalities of retinal function.  VEPs though are often abnormal.  Ichthyosis may involve the lids and periorbital areas.

Systemic Features: 

The skin changes are present at birth and consist of an ichthyosiform erythroderma.  Hyperkeratosis is also present at birth and full blown ichthyosis develops during infancy.  The skin changes are most marked about the neck, flexion creases, and lower abdomen.  Scales in these areas are often darker than the surrounding skin.  Mental retardation may be mild to severe and spastic diplegia or quadriplegia is common but there is little evidence of progression.  There does not seem to be any correlation of age with the severity of neurological disease.

Genetics

Mutations in the ALDH3A2 gene (17p11.2) are responsible for this autosomal recessive disorder resulting in a deficiency of fatty aldehyde dehydrogenase. This can lead to long-chain fatty alcohol accumulation as demonstrated in the brain with proton magnetic resonance spectroscopy.

A form of Sjogren-Larsson syndrome with more severe neurologic signs is caused by recessive mutations in ELOVL4 (6p14,1),  Mutations in the same gene have been identified in patients with autosomal dominant Stargardt disease 3 (600110).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disorder but moisturizing skin treatments can be beneficial.

References
Article Title: 

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: 

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: 

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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