autosomal recessive

Sandhoff Disease

Clinical Characteristics
Ocular Features: 

Retinal ganglion cells are rendered dysfunctional from the toxic accumulation of intra-lysosomal GM2 ganglioside molecules causing early visual symptoms.  These cells in high density around the fovea centralis create a grayish-white appearance.  Since ganglion cells are absent in the foveolar region, this area retains the normal reddish appearance, producing the cherry-red spot.  Axonal decay and loss of the ganglion cells leads to optic atrophy and blindness. 

Systemic Features: 

Sandhoff disease may be clinically indistinguishable from Tay-Sachs disease even though the same enzyme is defective (albeit in separate subunits A and B that together comprise the functional enzymes).  The presence of hepatosplenomegaly in Sandoff disease may be distinguishing. The infantile form of this lysosomal storage disease seems to be the most severe.  Infants appear to be normal until about 3-6 months of age when neurological development slows and muscles become weak.  Seizures, loss of interest, and progressive paralysis begin after this together with loss of vision and hearing.  An exaggerated startle response is considered an early and helpful sign in the diagnosis.  Among infants with early onset disease, death usually occurs by 3 or 4 years of age.   

Ataxia with spinocerebellar degeneration, motor neuron disease, dementia, and progressive dystonia are more common in individuals with later onset of neurodegeneration.  The juvenile and adult-onset forms of the disease also progress more slowly.  

Genetics

Sandhoff disease results from mutations in the beta subunit of the hexosaminidase A and B enzymes.  It is an autosomal recessive disorder caused by mutations in HEXB (5q13). 

Tay-Sachs disease (272800) can be clinically indistinguishable from Sandoff disease and they are allelic disorders.  However, the mutation in Tay-Sachs (272800) is in HEXA resulting in dysfunction of the alpha subunit of hexosaminidase A enzyme. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available beyond general support with proper nutrition and maintainence of airways.  Anticonvulsants may be helpful in some stages.  Gene therapy in fibroblast cultures has achieved some restoration of  hexosaminidase A activity in Tay-Sachs disease and may have potential in Sandhoff disease as well. 

References
Article Title: 

Donnai-Barrow Syndrome

Clinical Characteristics
Ocular Features: 

A number of ocular features have been described in this disorder, including telecanthus, hypertelorism, and iris hypoplasia with marked iris transillumination.  Myopia is commonly present and retinal detachments are a risk.  Several patients had iris colobomas.  Cataracts, small optic nerves, and macular hypoplasia have been reported as well.  The lid fissures usually slant downward. 

Systemic Features: 

The facial dysmorphology, in addition to the periocular malformations, includes a prominent brow or frontal bossing, posterior rotation of the ears, a flat nasal bridge and a short nose.  Sensorineural hearing loss is universal and at least some patients have complete or partial agenesis of the corpus callosum, and an enlarged anterior fontanel.  Diaphragmatic and umbilical hernias often occur together.  Low-molecular-weight proteinuria in the absence of aminoaciduria is a frequent feature.  Developmental delays are often seen but occasional patients have normal intellect.  Rare patients have seizures. 

Genetics

This is a rare autosomal recessive disorder caused by homozygous mutations in the LRP2 (low-density lipoprotein receptor-related protein 2 or megalin) gene located at 2q24-q31.  Some patients have an ocular phenotype resembling the Stickler syndrome (609508).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is focused on specific manifestations such as cataract and retinal detachment surgery. Patients need to be monitored throughout life for retinal disease.  Omphaloceles and diaphragmatic hernias need to be repaired.  Hearing aids may be beneficial. 

References
Article Title: 

Neuronal Ceroid Lipofuscinoses

Clinical Characteristics
Ocular Features: 

At least 13 genotypically distinct forms of neuronal ceroid lipofuscinosis have been described.  The ocular features are highly similar in all forms with blindness the end result in all types (although not all cases with an adult onset suffer vision loss).  The onset of visual signs and symptoms is highly variable.  Optic atrophy is the most common finding which may occur as early as two years of age in the infantile form.  Night blindness is a symptom in those with a later onset but panretinal degeneration with unrecordable ERGs eventually occurs.  Pigmentary changes throughout the retina are often seen and sometimes occur in a bull’s-eye pattern.  Retinal blood vessels may be attenuated and lens opacities of various types are common. 

Systemic Features: 

The neuronal ceroid lipofuscinosis are a group of inherited neurodegenerative lysosomal-storage disorders characterized by the intracellular accumulation of autofluorescent lipopigment causing damage predominantly in the central nervous system.  The result is a progressive encephalopathy with cognitive and motor decline, eventual blindness, and seizures with early death.  While early descriptions distinguished several types based primarily on age of onset, genotyping has now identified responsible mutations in at least 10 genes and time of onset is no longer considered a reliable indicator of the NCL type. 

Genetics

The NCLs are usually inherited in autosomal recessive patterns with the exception of some adult onset cases in which an autosomal dominant pattern is sometimes seen.

The various forms of NCL are often divided according to ages of onset but overlap is common.  Thus the congenital form (CLN10; 610127), caused by a mutation in the CTSD gene at 11p15.5, can have an onset of symptoms at or around birth but also is responsible for an adult form (Vida infra).  The CLN1 infantile form (256730), caused by a mutation in the PPT1 gene at 1p32, has an onset between 6 and 24 months  There are several mutations causing late infantile disease (CLN2, 204500) involving the TPP1 gene (11p15.5) leading to symptoms between 2-4 years, the CLN5 gene (256731) at 13q21.1-q32 with onset between 4 and 7 years, the CLN6 gene (601780) at 15q21-q23 showing symptoms between 18 months and 8 years, and the CLN8 gene (610003) at 8p23 with symptoms beginning between 3 and 7 years.  Another early juvenile form (CLN7; 610951) is caused by mutations in MFSD8 (4q228.1-q28.2).

A juvenile form (sometimes called Batten disease or Spielmeyer-Vogt with onset between 4 and 10 years results from mutations in CLN3 (204200) as well as in TPP1, PPT1, and CLN9 (609055).  An adult form known as ANCL or Kuf’s disease results from mutations in CTSD, PPT, CLN3, CLN5, and CLN4 (204300) and has its onset generally between the ages of 15 and 50 years. 

Homozygous mutations in the ATP13A2 gene (1p36.13), known to cause Kufor-Rakeb type parkinsonism (606693), have also been found in NCL.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Treatment is primarily symptomatic for sleep disorders, seizures, psychoses, malnutrition, dystonia and spasticity.  However, there is recent progress in the application of enzyme-replacement therapies in the soluble lysosomal forms of CNL.  Gene therapies and the use of stem cells also hold promise. 

References
Article Title: 

Hyperoxaluria, Primary, Type I

Clinical Characteristics
Ocular Features: 

About 30% of patients with type I develop retinopathy and about half of those have a diffuse optic atrophy.  Oxalate crystal deposition can cause a 'fleck retina' picture sometimes described as a crystalline retinopathy.  There is wide variation in the retinal phenotype.  Retinal toxicity leads to early and progressive vision loss.  The RPE may respond with hyperpigmentation in the form of 'ringlets' in the posterior pole.  Retinal fibrosis has been described.  Some patients develop choroidal neovascularization.

Evaluation using EDI-OCT shows progressive deposition of oxalate crystals throughout the retina, pigment epiithelium, and choroid.

Systemic Features: 

The onset of this disease can occur any time from infancy to 25 years of age.  Failure to thrive can be a presenting sign in infants.  Most patients have glycolic aciduria and hyperoxaluria as the result of failure to transaminate glyoxylate to form glycine.  The result is deposition of insoluble oxalate crystals in various body tissues with nephrolithiasis and nephrocalcinosis often early signs.  Neurologic, cardiac, vascular, and kidney disease is often the result although oxalate crystals can be found throughout the body.  Arteriole occlusive disease may lead to gangrene, Raynaud phenomena, acrocyanosis and intermittent claudication.  Renal failure is common. 

Genetics

Hyperoxaluria type I is an autosomal recessive disorder resulting from a mutation in the alanine-glyoxylate aminotransferase gene (AGXT) located at 2q36-q37.  Failure of this liver peroxisomal enzyme to transaminate glyoxylate results in oxidation of this molecule to form oxalate.

Hyperoxaluria type II (260000) is caused by mutations in the GRHPR gene (9cen) and type III (613616) by mutations in DHDPSL (HOGA1) (10q24.2).  Urolithiasis is the only clinical feature in these types. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Some patients benefit from oral pyridoxine (B6) treatment in type I hyperoxaluria.  Renal transplantation by itself is only temporarily helpful since the enzymatic defect remains and the donor tissue becomes damaged as well.  Combined renal-liver transplantation should be considered instead because it corrects the primary metabolic error and can even reverse the accumulation of oxalate crystals. 

References
Article Title: 

Primary hyperoxaluria in infants

Jellouli M, Ferjani M, Abidi K, Zarrouk C, Naija O, Abdelmoula J, Gargah T. Primary hyperoxaluria in infants. Saudi J Kidney Dis Transpl. 2016 May-Jun;27(3):526-32.

PubMed ID: 
27215245

Primary hyperoxaluria

Cochat P, Rumsby G. Primary hyperoxaluria. N Engl J Med. 2013 Aug 15;369(7):649-58. Review.

PubMed ID: 
23944302

Niemann-Pick Disease, Type C2

Clinical Characteristics
Ocular Features: 

The primary ocular feature of type C2 Niemann-Pick disease is supranuclear gaze palsy.  A cherry red spot is rarely seen. 

Systemic Features: 

Neurodegeneration is the outstanding clinical manifestation and often the cause of death.  The onset usually occurs in infancy and the course is rapid with death often in the first year of life.  The clinical disease is similar to that of the more common type C1 (257220) although there is considerable clinical heterogeneity in all types of NPC.  Pulmonary involvement can be a prominent feature of C2 disease.  Other neurologic symptoms include ataxia, facial dyskinesis, bradykinesia, expressive aphasia, dysarthria and cognitive decline.  Visceromegaly seems to be less common than in type C1 (257220).  Cholesterol esterification is impaired with accumulation in intracellular organelles. 

Genetics

Like other types of NPC disease, this disorder follows an autosomal recessive pattern of inheritance.  It results from mutations in the NPC2 gene (14q24.3).  These mutations are far less common than those in the NPC1 (257220)gene.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is available for symptoms such as seizures and dystonia.  Good pulmonary hygiene is important and precautions should be taken to prevent aspiration. 

References
Article Title: 

Walker-Warburg Syndrome

Clinical Characteristics
Ocular Features: 

The eyes are usually small and contain either retinal dysplasia or a congenital retinal detachment.  Colobomas, PHPV, cataracts, glaucoma, buphthalmos, anterior chamber dysgenesis, optic atrophy, and optic nerve hypoplasia have also been reported. 

Systemic Features: 

Hydrocephalus and congenital muscular dystrophy are the most important systemic features of these syndromes.  A Dandy-Walker malformation is often present.  Type II lissencephaly, cerebellar malformations and severe mental retardation are other features.  More variable signs include macro- or microcephaly, ventricular dilatation, cleft lip and/or palate, and congenital contractures.  WWS has a severe phenotype and death often occurs in the first year of life.  Brain histology shows severely disorganized cytoarchitecture and suggests a neuronal migration disorder. Microtia has been reported in several patients.

Most developmental milestones are delayed or never achieved and death may occur in early childhood. 

Genetics

The MDDGs (muscular dystrophy dystroglycanopathies) comprise a genetically and clinically heterogeneous group of disorders (sometimes called muscle-eye-brain disease) of which the A types are more severe than the B types.  The mutant genes responsible are involved in glycosylation of DAG1 (alpha-dystroglycan). 

Types A1 (MDDGA1; 236670), B1 (MDDGB1; 613155) and C1 (MDDGC1; 609308) result from mutations in a gene known as POMT1 (9p34.1).  The muscular dystrophy in type C1 is of the limb-girdle type LGMD2K.

A2 (MDDGA2; 613150) is caused by mutations in POMT2 (14q24.3).  Mutations in POMT2 may also cause the less severe muscle-eye-brain disease (MEB) type B2 (MDDGB2; 613156), and a similar disease (C2) in which the muscle dystrophy is of the limb-girdle type LGMD2N and eye findings may be absent (MDDGC2; 613158).

Mutations in POMGNT1 (1p34-p33) cause type A3 (MDDGA3; 253280) and type B3 (MDDGB3; 613151).  The muscular dystrophy in B3 is of the limb-girdle type.  POMGNT1 mutations may be associated with congenital glaucoma, retinal dysplasia, and high myopia. Type C3 (MDDGC3; 613157), also with a limb-girdle type of muscular dystrophy (LGMD2O), is caused by mutations in POMGNT1 as well.

FKTN mutations cause type A4 MDDG (MDDGA4; 253800) associated with the Fukuyama type of congenital muscular dystrophy but they can also cause type B4 (MDDGB4; 613152) which does not have mental retardation, and type C4 (MDDGC4; 611588) with seizures and a limb-girdle type (LGMD2M) of muscular dystrophy.

Types A5 (MDDG5A; 613153) and B5 (MDDGB5; 606612) are the result of mutations in the FKRP gene (19q13.3).  Of the two the latter is the less severe and the muscular dystrophy is of the limb-girdle type.  The eyes may be microphthalmic and have retinal pigmentary changes and congenital glaucoma.

Type A6 (MDDGA6; 613154) and B6 (MGGDB6; 608840) are caused by mutations in the LARGE gene (22q12.3).  MDDGA7, or type A7 (614643) results from homozygous or compound heterozygous mutations in the ISPD gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available but early indications are that FKRP gene therapy restores functional glycosylation and improves muscle functions.

References
Article Title: 

Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study

Mercuri E, Messina S, Bruno C, Mora M, Pegoraro E, Comi GP, D'Amico A, Aiello C, Biancheri R, Berardinelli A, Boffi P, Cassandrini D, Laverda A, Moggio M, Morandi L, Moroni I, Pane M, Pezzani R, Pichiecchio A, Pini A, Minetti C, Mongini T, Mottarelli E, Ricci E, Ruggieri A, Saredi S, Scuderi C, Tessa A, Toscano A, Tortorella G, Trevisan CP, Uggetti C, Vasco G, Santorelli FM, Bertini E. Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology. 2009 May 26;72(21):1802-9.

PubMed ID: 
19299310

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: 

Albinism, Oculocutaneous, Type III

Clinical Characteristics
Ocular Features: 

The irides may be multicolored with the central potion light brown and the peripheral areas blue-gray.  Translucency of a punctate and radial nature is present.  Nystagmus is present in almost all cases and strabismus is present in nearly half.  Visual acuity is in the range of 20/60 to 20/200.   Photophobia is less severe than in other types of oculocutaneous albinism, possibly because the vast majority of individuals (86%) have some pigmentation in the fundus. 

Systemic Features: 

The hair in dark-skinned people may be medium brown while the skin is often light brown and subject to faint tanning.  However, the hair is often copper-red in color which has given rise to the designation rufous oculocutaneous albinism. 

Genetics

This tyrosinase-positive type of albinism is sometimes called 'rufous' (ROCA) or 'brown' (BOCA) oculocutaneous albinism and is frequently found in dark-skinned individual such as Africans, African-Americans, and Hispanics.  Like other types it is inherited in an autosomal recessive pattern.  Mutations in the tyrosinase-related protein-1, TYRP1 (9p23), are responsible which seems to lead to an arrest in melanin maturation and a decrease in the amount of insoluble melanin in melanocytes.

Other autosomal recessive types of oculocutaneous albinism are: OCA1 (203100, 606952), OCA2 (203200), and OCA4 (606574). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the hypopigmentation.  However, precautions against excessive sun exposure are advised.  Low vision aids can be helpful. 

References
Article Title: 

Oculocutaneous albinism

Gronskov K, Ek J, Brondum-Nielsen K. Oculocutaneous albinism. Orphanet J Rare Dis. 2007 Nov 2;2:43. Review.

PubMed ID: 
17980020

Albinism, Oculocutaneous, Type IV

Clinical Characteristics
Ocular Features: 

The ocular manifestations in type IV oculocutaneous albinism are similar to those of other types.  Nystagmus, strabismus, misrouting of neuronal axons, and foveal hypoplasia are prominent features although there is some clinical heterogeneity among patients.  Nystagmus may not be present at birth but is almost always evident by 3-4 months of age.  The iris may be pale blue or tan and does not generally darken with age.  Poor stereopsis is common.  Vision is stable after childhood and usually in the range of 20/100-20/400. 

Systemic Features: 

Hair color is generally intermediate between white and brown but many patients have only white hair and in others the hair is brown.  Little darkening occurs as patients become older.  The skin is often white or creamy yellow. 

Genetics

This type of oculocutaneous albinism is one of the more common types found among Japanese and maybe Chinese individuals although it has also been reported in German and Turkish individuals.  This is a rare autosomal recessive form of albinism caused by mutations in the MATP (SLC45A2) gene located at 5p13.3. 

A single Japanese family with 16 affected members has been reported in which the transmission pattern was consistent with autosomal dominant inheritance. Heterozygous mutations in the SLC45A2 gene segregated appropriately.

Other types include OCA1 (203100, 606952 ), OCA2 (203200 ), OAC3 (203290), OAC5 (615179), and OCA6 (113750)..

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the hypopigmentation.  Low vision aids and tinted lenses may help some patients.  Exposure to the sun should be limited. 

References
Article Title: 

Oculocutaneous albinism

Gronskov K, Ek J, Brondum-Nielsen K. Oculocutaneous albinism. Orphanet J Rare Dis. 2007 Nov 2;2:43. Review.

PubMed ID: 
17980020

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