autosomal recessive

Smith-Lemli-Opitz Syndrome

Clinical Characteristics
Ocular Features: 

A large number of ocular anomalies have been found in SLO syndrome but the most common is blepharoptosis of some degree.  No consistent pattern of ocular abnormalities has been reported.  Atrophy and hypoplasia of the optic nerve, strabismus, nystagmus, and cataracts may be present.   Abnormally low concentrations of cholesterol and cholesterol precursors have been found in all ocular tissues studied.

Systemic Features: 

This is a syndrome of multiple congenital anomalies.  Among these are dwarfism, micrognathia, hard palate anomalies, hypotonia, anomalies of the external genitalia, polysyndactyly, microcephaly, and mental retardation.  It has been suggested that many individuals have a characteristic behavioral profile consisting of cognitive delays, hyperreactivity, irritability, language deficiency, and autism spectrum behaviors.  Some individuals exhibit aspects of self destructive behavior.  Tissue levels of cholesterol are low.

Genetics

SLO syndrome is an autosomal recessive disorder resulting from mutations in the sterol delta-7-reductase  (DHCR7) gene mapped to 11q12-q13. The result is a defect in cholesterol synthesis.

The clinical features significantly overlap those seen in Meckel (249000) and Joubert (213300) syndromes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

A high cholesterol diet has been reported to have a beneficial effect on behavior and general well-being.

References
Article Title: 

Optic Atrophy 6

Clinical Characteristics
Ocular Features: 

Visual impairment is often noted under the age of 6 years.  The disease is bilateral and loss of vision procedes slowly, eventually reaching 20/100 to 20/200.  Moderate photophobia and dyschromatopsia are present but nystagmus is absent.  The impact on the visual field seems to be minimal and limited to decreased sensitivity in the central areas.

Systemic Features: 

No systemic abnormalities are associated.

Genetics

Evidence for this presumed autosomal recessive type of optic atrophy is based on a single large, consanguineous French Canadian family.  A locus in the 8q21-q22 region presumably containing the mutant gene, designated OPA6, was found.  Linkage analysis excluded genes linked to autosomal dominant optic atrophy.

Another autosomal recessive optic atrophy disorder (OPA7; 612989) has also been reported.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment beyond low vision aids is helpful.

References
Article Title: 

Cerebrooculofacioskeletal Syndrome

Clinical Characteristics
Ocular Features: 

Congenital cataracts and microphthalmia are frequent findings in this disorder.  Delayed mental development and early death in childhood have limited full delineation of the ocular phenotype.  Photosensitivity, nystagmus, optic nerve atrophy, and pigmentary retinopathy have been reported.  The eyes may appear deeply-set.

Systemic Features: 

Microcephaly, flexion contractures, prominent nasal root and an overhanging upper lip are common features.  Severe developmental and growth delays are evident early followed by progressive behavioral and intellectual deterioration.  Both hypotonia and hyperreflexia have been described.    Kyphosis and scoliosis are common.  CT scans may show intracranial calcifications and brain histology shows severe neurodegeneration with neuronal loss and gliosis.  Respiratory distress may also occur and some individuals have died in the first decade of life.

Genetics

Homozygous mutations in the ERCC6 gene (10q11) seem to be responsible for this autosomal recessive disorder.  Several sets of parents have been consanguineous.  Mutations in the same gene are responsible for Cockayne type B syndrome (133540) and some suggest that the variable phenotype represents a spectrum of disease rather than individual entities. Cerebrooculofacioskeletal syndrome represents the more severe phenotype in this spectrum.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disorder.

References
Article Title: 

Manitoba Oculotrichoanal Syndrome

Clinical Characteristics
Ocular Features: 

The ocular phenotype has not been completely defined because of the limited number of families reported.    Colobomas, unilateral and bilateral, of the upper eyelids seems to be the most consistent finding. Clinical hypertelorism is also a common finding. Nasolacrimal duct obstruction, unilateral clinical anophthalmia, cryptophthalmos, and a cloudy cornea have also been reported.

Systemic Features: 

The anterior scalp hairline is abnormally low, sometimes extending to the eyebrows.  The anus is anomalous and may be stenotic in some cases.  The nasal tip is often broad and has a notch.  Several patients had omphaloceles.

Genetics

Autosomal recessive inheritance has been assumed as no direct transmission from parent to child has been reported, and most affected individuals (including sibs) have been found in an isolated population of Manitoba Indians with a high rate of consanguinity.  Homozygous deletions of exons 8-23 in FREM1 as well as simple 4bp deletions (9p22.3) have been found in several families confirming the presumed autosomal recessive mode of inheritance.

 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Lid colobomas and anal stenosis should be repaired.

References
Article Title: 

Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1

Slavotinek AM, Baranzini SE, Schanze D, Labelle-Dumais C, Short KM, Chao R, Yahyavi M, Bijlsma EK, Chu C, Musone S, Wheatley A, Kwok PY, Marles S, Fryns JP, Maga AM, Hassan MG, Gould DB, Madireddy L, Li C, Cox TC, Smyth I, Chudley AE, Zenker M. Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1. J Med Genet. 2011 Jun;48(6):375-82.

PubMed ID: 
21507892

Homocystinuria, MTHFR Deficiency

Clinical Characteristics
Ocular Features: 

The ocular signs in MTHFR deficiency are likely similar to those found in beta-synthase deficiency (236200) but no comparative study has been reported.  Ectopia lentis is common and the high mobility of the lens carries a significant risk of pupillary block glaucoma and migration into the anterior chamber.

Systemic Features: 

There is a wide range in clinical disease in MTHFR deficiency but the neurological signs and the progressive of disease seem to be more aggressive than in beta-synthase deficiency (236200) . Neonates may have seizures and failure to thrive but other affected patients may live to adulthood without symptoms.  Early death from neurological complications is more common and the mental retardation is apparently more severe.  There is a serious risk for thromboembolic events which may be life-threatening.  Hyperhomocyteinemia and low plasma methionine are present as is increased homocystine in urine.

Genetics

Mutations in MTHFR (1p36.3) are responsible for this form of homocystinuria.  Another form, beta-synthase deficiency (236200), is caused by a mutation in the CBS  gene (21q22.3).  This is an autosomal recessive disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Administration of betaine has been reported to reduce the neurological disease but it must be started early before brain damage occurs.  It does not correct hyperhomocysteinemia nor does it correct CNS MTHFR deficiency.  It has also been reported that betaine in combination with folic acid and cobalamin can prevent symptoms.

References
Article Title: 

Mutation Update and Review of Severe MTHFR

Froese DS, Huemer M, Suormala T, Burda P, Coelho D, Gueant JL, Landolt MA,
Kozich V, Fowler B, Baumgartner MR. Mutation Update and Review of Severe MTHFR
Deficiency. Hum Mutat. 2016 Feb 13.

PubMed ID: 
2687264

Homocystinuria, Beta-Synthase Deficiency

Clinical Characteristics
Ocular Features: 

More than half of patients have ectopia lentis by the age of 10 years and the dislocation is progressive.  Ectopia lentis occurs in 90% of patients and 94% of these are noted by the age of 20 years.  The lenses seem to be more mobile than those in Marfan syndrome with a significantly increased risk of lens migration into the anterior chamber (19%) or complete dislocation into the posterior chamber (14%).   Lens surgery is required in homocystinuria about 7 years earlier than in Marfan syndrome with 62% of procedures necessitated by pupillary block glaucoma or displacement into the anterior chamber.  Whereas nearly 70% of lenses dislocate superiorly in Marfan syndrome, only 9% of homocystinuria lenses do so.

Other ocular features include optic atrophy (23%), iris atrophy (21%), anterior staphylomas (13%) and corneal opacities (9%).  Retinal detachments occur in 5-10%.  The majority of patients both pre- and postoperatively have vision of 20/50 or worse.

Systemic Features: 

Arachnodactyly and tall stature in some patients may suggest Marfan syndrome.  Mental deficiencies or behavioral problems are present in a majority of patients (50-60%) with mental functioning higher in the subset of patients who are B6-responsive.  Thromboembolic events (strokes, myocardial infarctions) are a significant risk at any age, especially so after age 20 years, and this is responsible for considerable morbidity and mortality.  The risk is especially high following general anesthesia unless hydration is strictly controlled.  Osteoporosis and seizures are common.  Hypopigmentation is often present but darkening of hair has been noted following pyridoxine treatment.  Serum homocysteine is generally elevated and the urine contains elevated levels of methionine.

Genetics

Classic homocystinuria is an autosomal recessive disorder that results from mutations in the CBS (21q22.3) gene encoding cystathionine beta-synthase.  It is the second most common error of amino acid metabolism.  Numerous mutations have been identified but among the most common ones are I278T which causes a pyridoxine-responsive disorder, and the G3307S mutation which leads to a variant that is not responsive to pyridoxine treatment.

For another more aggressive form of homocystinuria caused by mutations in MTHFR (1p36.3) see Homosystinuria, MTHER Deficiency (236250).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Patients with this disorder form two groups: those who respond to pyridoxine (vitamin B6) and those who do not.  Those who do not respond to B6 tend to have more severe disease.  Methionine restriction administered neonatally has been reported to prevent mental retardation and reduce the rate of lens dislocation.  Neonates should be treated with B6 therapy, protein and methionine restriction, betaine, and folate with vitamin B12 supplementation.  Surgical removal of lenses may be required but the rate of vitreous loss is high.

References
Article Title: 

Osteoporosis-Pseudoglioma Syndrome

Clinical Characteristics
Ocular Features: 

Retrolental masses often present at birth have been mistaken for retinoblastomas.  Hyperplasias of the vitreous, corneal opacities, and secondary glaucoma have been described.  Band keratopathy may account for some of the corneal clouding and opacities.  Most patients are blind soon after birth although some retain some vision into the second decade.

Systemic Features: 

Some patients have been described as mentally retarded but others have normal intelligence.  Hypotonia and hyperflexible joints have been noted.  Bone fractures are common sometimes resulting in scoliosis, short stature and limb deformities.  Radiography of the skeletal reveals porotic and thin bones.

Genetics

This disorder, sometimes called the ocular form of osteogenesis imperfecta, results from mutations in LRP5 (11q13.4).  The same gene is mutant in the EVR4 type of familial exudative vitreoretinopathy (601813) which has some of the same ocular and bone features.  Most descriptions of OPPG were published before the gene mutation was found and many reports do not include detailed ocular examinations.  Certainly the two disorders are allelic and likely the same condition. 

Mutations in LRP5 lead to EVR4 disease in both the heterozygous and homozygous configuration but most cases of OPPG have homozygous or compound heterozygous mutations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Bone fractures need to be repaired and glaucoma treated when present.  Bisphosphonate treatment may lead to increased bone density if initiated early.  The retrolental masses need to be carefully evaluated to rule out retinoblastoma.

References
Article Title: 

Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13

Gong Y, Vikkula M, Boon L, Liu J, Beighton P, Ramesar R, Peltonen L, Somer H, Hirose T, Dallapiccola B, De Paepe A, Swoboda W, Zabel B, Superti-Furga A, Steinmann B, Brunner HG, Jans A, Boles RG, Adkins W, van den Boogaard MJ, Olsen BR, Warman ML. Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13. Am J Hum Genet. 1996 Jul;59(1):146-51.

PubMed ID: 
8659519

Peroxisome Biogenesis Disorder 1A (Zellweger)

Clinical Characteristics
Ocular Features: 

Ocular signs resemble those of other peroxisomal disorders with cataracts and retinopathy.  The lethal consequences of ZWS have hampered delineation of the full spectrum of ocular manifestations but many infants have these features plus optic atrophy and horizontal nystagmus.  Most infants do not follow light.  Pupillary responses may be normal in early stages but disappear later. Hypertelorism has been described but metrics are often normal.

Systemic Features: 

Many infants have hepatomegaly at birth and may develop splenomegaly as well.  Jaundice often occurs with intrahepatic biliary dysgenesis.   Severe hypotonia is present at birth but improves in those patients who survive for several years.  Psychomotor retardation can be profound and seizures may occur but sensory examinations are normal.  Most infants have a peculiar craniofacial dysmorphology with frontal bossing, large fontanels, and wide set eyes.  Pipecolic acid levels are low in serum and absent in the CSF.  Most infants do not survive beyond 6 months of age.

 

Genetics

This is a peroxisome biogenesis disorder with a complex biochemical profile resulting from a large number of mutations in at least 13 PEX genes.  It is inherited in an autosomal recessive pattern.

What was formerly called Zellweger Syndrome is now more properly called Zellweger Spectrum Disorder, or sometimes a peroxisomal biogenesis disorder in the Zellweger spectrum of disorders.  The spectrum also includes neonatal adrenoleukodystrophy (601539) and Infantile Refsum disease (601539). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available.

References
Article Title: 

Peroxisome Biogenesis Disorder 1B (neonatal adrenoleukodystrophy)

Clinical Characteristics
Ocular Features: 

This peroxisomal disorder presents in the first year of life with both systemic and ocular features.  Night blindness is the major ocular feature and at least some have optic atrophy similar to the adult form.  Central acuity is reduced secondary to macular degeneration.  A pigmentary retinopathy is frequently present and often follows the appearance of whitish retinal flecks in the midperipheray.  Nystagmus and cataracts are common features.  Reduction or absence of ERG responses can be used in young children to document the retinopathy.  Blindness and deafness commonly occur in childhood.

Systemic Features: 

This disorder is classified as a leukodystrophy, or disease of white matter of the brain, associated with the breakdown of phytanic acid.  Ataxia and features of motor neuron disease are evident early.  Hepatomegaly and jaundice may also be early diagnostic features as bile acid metabolism is defective.  Infant hypotonia is often seen.  Nonspecific facial dysmorphism has been reported.  The ears are low-set and epicanthal folds are present.  The teeth are abnormally large and often have yellowish discoloration.  Postural unsteadiness is evident when patients begin walking.  Diagnosis can be suspected from elevated serum phytanic and pipecolic acid (in 20% of patients) or by demonstration of decreased phytanic acid oxidation in cultured fibroblasts.  Other biochemical abnormalities such as hypocholesterolemia, and elevated very long chain fatty acids and trihydroxycholestanoic acid are usually present.  Anosmia, developmental delays, and mental retardation are nearly universal features.  Early mortality in infancy or childhood is common.

Genetics

This is a genetically heterogeneous disorder of peroxisome biogenesis caused by mutations in at least three genes, PEX1 (7q21-q22), PEX2 (8q21.1), and PEX6 (22q11-21).  Each is inherited in an autosomal recessive pattern.  The mechanism of disease is different from the classic or adult Refsum disorder (266500) and some have debated whether the term ‘infantile Refsum disease’ is appropriate.

This disorder shares some clinical features with other peroxisomal disorders such as Zellweger syndrome (214100) and rhizomelic chondrodysplasia punctata (215100).  Zellweger syndrome (214100), neonatal adrenoleukodystrophy and infantile Refsum disease (601539) are now considered to be peroxisomal biogenesis or Zellweger spectrum disorders.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

Refsum Disease, Adult

Clinical Characteristics
Ocular Features: 

A retinitis pigmentosa-like retinopathy is the major ocular manifestation of this disease.  There is typical night blindness and visual field constriction.   Rod ERG responses are usually subnormal.  However, central acuity is also reduced due to a degenerative maculopathy.   Cataracts and optic atrophy are common.  The macula may undergo progressive degeneration and optic atrophy is not uncommon.  Some patients have defective pupillary responses.

Systemic Features: 

Onset of symptoms is usually late in the first decade and sometimes into the third decade.  There is usually a polyneuropathy with impaired motor reflexes and paresis in the limbs.  A progressive sensorineural hearing loss occurs in many patients.  Sensory deficits also occur.  Some have ataxia and skin changes of ichthyosis.  Anosmia is a near universal feature.  Heart failure may occur and cardiac abnormalities such as conduction defects can occur.  A variety of skeletal abnormalities such as pes cavus, short fourth metatarsals, and evidence of epiphyseal dysplasia have been reported.  There is considerable clinical heterogeneity even within families.

Phytanic acid oxidase activity as measured in fibroblasts is often low while serum phytanic acid is increased.  The cerebrospinal fluid contains increased protein but no increase in cells.

Genetics

This disorder results from mutations in the PHYH (PAHX) gene (10pter-p11.2) encoding phytanoyl-CoA hydroxylase, or, more rarely in PEX7 (6q22-q24) encoding peroxin-7 resulting in an uncommon condition (10% of cases) sometimes called adult Refsum disease-2. 

Mutations in the latter gene also cause rhizomelic chondrodysplasia punctata type 1 (215100) which does not have all of the neurological features or the retinopathy.

There is also so-called infantile form of Refsum disease (266510).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

A diet low in phytanic acid can lead to improvement in the neurologic symptoms such as the ataxia and polyneuropathy but must be instituted in early stages of the disease.  This approach may not be as beneficial for the visual or auditory symptoms.

References
Article Title: 

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