Lenz microphthalmia syndrome is a rare X-linked recessive condition first described by Lenz in 1955 and comprises of anophthalmia, microcephaly, mental retardation, external ear, digital, cardiac, skeletal, and urogenital anomalies. We present three brothers (ages 15 years, 9 years, and 18 months) and a maternal uncle (age 27 years) with congenital anophthalmia, delayed motor development, hypotonia, and moderate to severe mental retardation. They also have abnormally modeled ears, high-arched palate, pectus excavatum, finger and toe syndactyly, clinodactyly, fetal pads, scoliosis, cardiac, and renal abnormalities. An obligate carrier had abnormally modeled ears and syndactyly of the 2nd to 3rd toes bilaterally. Linkage and haplotype analysis in this family indicates that the gene is located in a 17.65-cM region on chromosome region Xq27-Xq28.

Lenz syndrome is a rare X-linked recessive syndrome first described by Lenz in 1955. Clinical features include anophthalmia, microcephaly, mental retardation, cardiac, skeletal, urogenital, external ear, and digital, anomalies. We present three brothers (ages 15 years, 9 years, and 18 months) and a maternal uncle (age 27 years) with congenital anophthalmia, hypotonia and moderate to severe mental retardation. Dysmorphic features include dysplastic ears, high arched palate, pectus excavatum, finger and toe syndactyly, clinodactyly and fetal pads. Other features include scoliosis, cardiac and renal abnormalities. Obligate carriers have a history of recurrent spontaneous losses. One carrier has dysplastic ears and syndactyly of the 2-3rd toes bilaterally; features which may be helpful in identification. Fourteen previously reported cases were additionally reviewed. Mental retardation was present in 100%, 93% had growth retardation, 69% had microcephaly, 88% had ear anomalies, 76% had dental anomalies, 12% had a congenital heart defect, 50% had a urogenital anomaly, 47% had a spinal deformity and 69% had anomalies of the fingers or toes. Linkage and haplotype analysis in this family indicates that the gene is located in a 17.65 cM region on chromosome Xq27-Xq28 flanked by microsatellite markers DXS1232 and DXS8043. This region overlaps the anopthalmos locus ANOP1, but excludes the OCRL locus for Lowe oculocerbrorenal syndrome. Candidate genes involved in neuronal development that map to this critical interval include CXORF1 and KIAA0006. This is the first report of linkage analysis in Lenz microphthalmia a unique disorder associated with mental retardation and multiple anomalies.

We have previously reported a new autosomal dominant inclusion body myopathy clinically resembling limb girdle muscular dystrophy, associated with Paget disease of bone in the majority and frontotemporal dementia in a third of individuals. The critical locus for this unique disorder now termed IBMPFD is 9 p21.1-p12, spans 5.5 Mb and contains the gene responsible for the recessive quadriceps-sparing inclusion body myopathy (IBM2). Mutation analysis of the GNE gene associated with IBM2 in affected individuals from four IBMPFD families did not identify any mutations, indicating that the two disorders are not allelic. Expression studies indicate that GNE has a tissue-specific splice pattern, with four splice variants. Mutation analysis in three other candidate genes (beta-tropomyosin, NDUFB6 and SMU1) did not identify any mutations.

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of polyneuropathies characterized by degeneration of peripheral nerves, resulting in distal muscle atrophy, sensory loss, and deformities of hands and feet. We have studied 34 individuals in a large 84-member four-generation central Illinois family with autosomal dominant Charcot-Marie-Tooth and deafness. Nerve conduction velocities are consistent with type 1 CMT. Audiological evaluation revealed both auditory neuropathy and cochlear involvement in affected individuals. There is increasing clinical severity and younger age of onset of CMT and deafness with each progressive generation, suggestive of anticipation (P < 0.05). The proband, a female diagnosed at birth with hypotonia, bilateral vocal cord palsy, swallowing incoordination, and hearing impairment, died at age 18 months. Another individual died at the age of 3 months from hypotonia later attributed to CMT. Genetic analysis indicated that affected individuals in this family do not have the common 1.4 Mb duplication associated with type 1A CMT; however, all affected individuals have a unique G to C transversion at position 248 in coding exon 3 of the peripheral myelin PMP22 gene located on chromosome 17p11.2-p12. This mutation is predicted to cause an Ala67Pro substitution in the second transmembrane domain of PMP22, consistent with the molecular cause of the CMT phenotype. However, it does not explain the cochlear component of the deafness, the clinical observation of anticipation, and other features in this family.