autosomal recessive

Charcot-Marie-Tooth disease can also be classified on the basis of their hereditary patterns including autosomal dominant, autosomal recessive, X-linked recessive, and X-linked dominant.  Each of these contains yet more distinct subtypes as defined by mutations in at least 40 genes.

The wide range of disease severity and the overlapping of many signs can make pedigree construction and the determination of recurrence risks and prognosis challenging.  The only recourse may be genotyping.

See Charcot-Marie-Tooth Disease with Glaucoma (604563) for a form of this disease in which glaucoma occurs early.

Congenital retinal nonattachment consists of a group of sometimes familial conditions for which no responsible gene has been identified.  In a genomic study of 21 consanguineous NCRNA Pakistani families 3 had mutations in ATOH7 and 10 had mutations in familial exudative vitreoretinopathy genes.  Genotyping did not reveal associated mutations in the remaining 38% of these families. It is likely that multiple entities are represented but until the molecular etiologies are identified, no more specific classification is possible.

Studies in mice document that the Atoh7 gene is important to retinal ganglion cell neurogenesis.  In humans, both autosomal recessive PHPV and congenital nonattachment of the retina are associated with microsatellite linkage and haplotype matching to a region at 10q21 adjacent to the ATOH7 gene but so far no causative mutation has been found in this region.  However, studies in large consanguineous kindreds in which a deleted DNA segment adjacent to ATOH7 segregated with the NCRNA phenotype suggest that a transcription regulator may be at fault in the timing and level of ATOH7 expression.

The disorder known as persistent hyperplastic primary vitreous is generally not considered hereditary since it usually occurs unilaterally and sporadically.  It is sometimes found in association with a number of syndromal conditions as well.  However, it has also been reported in familial patterns consistent with both autosomal recessive and autosomal dominant patterns.  DNA mapping of individuals with bilateral disease found in a consanguineous Pakistani kindred with presumed autosomal recessive disease suggests that a locus at 10q11-q21 may be responsible.

Evidence for autosomal dominant inheritance of persistent hyperplastic primary vitreous comes from rare families with an apparent vertical transmission of the condition.

Congenital nonattachment of the retina is also seen in the osteoporosis-pseudoglioma syndrome (250770).  However, this is a syndromal disorder with neurologic and joint disease in addition to porotic, thin, fragile bones (sometimes called the ocular form of osteogenesis imperfecta) resulting from mutations in LRP5 on chromosome 11.

This infantile-onset form of spinocerebellar atrophy results from homozygous or compound heterozygous mutations in the C10ORF2 gene (10q24) which encodes the so-called Twinkle and Twinky mitochondrial proteins. Since the Twinkle protein is involved in the production and maintenance of mitochondrial DNA, its malfunction leads to reduced quantities of mtDNA in the liver and CNS but not in skeletal muscle.

Mutations in the C10ORF2 gene affecting the Twinkle protein may be responsible for an autosomal dominant progressive ophthalmoplegia (609286) in which ptosis and cataracts are often found but the more extensive muscle and sensory deficits are often missing.  This is one of the better examples of seemingly unique, allelic phenotypes resulting from different mutations in the same gene.

This is an autosomal recessive condition secondary to homozygous mutations in TPP1(11p15).

The same gene is mutated in neuronal ceroid lipofuscinosis 2 (CLN2, 204500), a far more serious condition with epilepsy, optic atrophy, retinal degeneration, and a rapidly progressive course leading to early death in many individuals. It has been suggested that mutations resulting in the more severe CLN2 phenotype completely or nearly completely abolish TPP1 enzyme activity whereas those that cause SCAR7 simply result in diminished activity.

A variety of mutations in the CRYAA (21q22.3) have been reported in a several ethnic groups.  Most pedigrees are consistent with autosomal dominant inheritance but autosomal recessive inheritance has been suggested in other families.