INCLUDED
PEROXISOME BIOGENESIS DISORDER, PEX7-RELATED, ATYPICAL PEROXISOME BIOGENESIS DISORDER, COMPLEMENTATION GROUP 11, INCLUDED
REFSUM DISEASE, ADULT, 2
CG11, INCLUDED
PEROXISOME BIOGENESIS DISORDER, COMPLEMENTATION GROUP R, INCLUDED
CGR
PBD9B
While most patients of PBD complementation group 11 manifest rhizomelic chondrodysplasia punctata (RCDP1; 215100), a few have been reported with unusually mild phenotypes with longer survival, less neurologic involvement, normal or near-normal growth, and absence of rhizomelia (Braverman ... While most patients of PBD complementation group 11 manifest rhizomelic chondrodysplasia punctata (RCDP1; 215100), a few have been reported with unusually mild phenotypes with longer survival, less neurologic involvement, normal or near-normal growth, and absence of rhizomelia (Braverman et al., 2002). In some cases this phenotype was indistinguishable from that of classic Refsum disease (266500) and patients carried this diagnosis. Individuals with PBDs of complementation group 11 (CG11, equivalent to CGR) have mutations in the PEX7 gene. For information on the history of PBD complementation groups, see 214100.
Moser et al. (1995) reported 3 patients of PBD CG11 with unusually mild clinical and biochemical manifestations. Two sisters had congenital cataracts but no dysmorphic features and normal limbs. The older sister had normal cognitive function, and the ... Moser et al. (1995) reported 3 patients of PBD CG11 with unusually mild clinical and biochemical manifestations. Two sisters had congenital cataracts but no dysmorphic features and normal limbs. The older sister had normal cognitive function, and the younger was mentally retarded, functioning at 5 years of age at an 18-month to 2-year-old level. A moderate elevation of levels of phytanic acid in plasma and intermediate reductions in erythrocyte plasmalogen levels and fibroblast plasmalogen synthesis pointed to peroxisome dysfunction. In fibroblasts the reduced capacity to oxidize phytanic acid and the moderate reduction in plasmalogen synthesis, in combination with normal VLCFA levels, suggested a relationship to RCDP that was confirmed by complementation studies. The third patient, a Norwegian man 55 years old at the time of the report, at age 9 had retinitis pigmentosa, polyneuropathy, ichthyosis, hearing loss, and normal cognitive function, and had been diagnosed with classic Refsum disease (266500) by Professor Sigvald Refsum. When he was 26 years of age plasma phytanic acid levels were elevated and he was given a phytanic acid-restricted diet. At age 53 his neurologic disability had worsened and he had also developed cardiomyopathy. He had not adhered to the diet by plasma phytanic acid levels were only slightly increased. Except for a reduction in the capacity to oxidize phytanic acid, peroxisomal functions in fibroblasts were normal. Barth et al. (1996) studied a 9-year-old girl with cataracts and atypical bone dysplasia. Neurologic findings were mild compared to classic RCDP. Plasma phytanic acid was normal. Results of de novo plasmalogen synthesis and phytanic acid oxidation studied in cultured skin fibroblasts were intermediate between normal controls and classic RCDP. Peroxisomal thiolase was present only in the unprocessed 44-kD protein. That this was a mild variant of classic RCDP was supported further by complementation studies. Earlier studies had shown that fibroblasts from all RCDP patients belong to a single complementation group. Fibroblasts from this patient likewise fell into this complementation group. The patient had been considered normal until 3 months of age when her mother noticed that her legs could not be straightened. Flexion contractures of the hips, elbows, and knees were found at 1 year. Bilateral cataracts necessitated lens extraction at 2 years. She did not walk independently until 8 years of age. Speech development and adaptive behavior at 8 years represented a mental age between 1 and 2 years. Review of x-ray findings of the knees at the age of 10 months showed irregular calcific stippling outlining the patellas. This stippling had disappeared on repeat examination at 5 years. The length of the humeri and femora were very short with the shortness of the femora not explained by the dysplasia of the hips. Braverman et al. (2002) reported 5 patients with PEX7 mutations and atypically mild phenotypes. One, aged 58 years (PBD147), had a phenotype indistinguishable from that of classic Refsum disease. The second had bilateral cataracts but otherwise normal exams. The third presented in infancy with moderate developmental delay, epiphyseal irregularities on skeletal x-rays, and poor growth. He developed features of adult Refsum disease at age 12 years. The fourth patient at the age of 3 years had moderate mental impairment, cataracts, and chondrodysplasia punctata but is without rhizomelia or growth failure. The fifth patient, age 9 years, had cataracts, chondrodysplasia, and severe mental deficiency but no rhizomelia or growth failure. Horn et al. (2007) reported follow-up of a man with Refsum disease (PBD147 in the report of Braverman et al. (2002)) originally diagnosed by Dr. Refsum in 1948 and reported again by Eldjarn et al. (1966). He presented at age 7 years with all of the classic clinical features, including progressive retinopathy with loss of night vision and concentric narrowing of the visual fields. Pupils were small and irregular in shape and showed impaired response to light stimulation. He had neurogenic hearing loss and anosmia. A chronic sensorimotor neuropathy manifest as lower limb atrophy, lack of distal reflexes, and impaired distal sensation. Subcutaneous nerves were thickened and palpable. There was a history of ichthyosis, and he had hammertoe deformity. Long-term dietary restriction of phytanic acid intake stabilized his progressive loss of vision and hearing. However, at age 40, he developed progressive cardiac disease with arrhythmias and heart failure necessitating cardiac transplant at age 58. Van den Brink et al. (2003) reported 2 probands with Refsum disease. The first proband originated from a family comprising 8 sibs and was 1 of 3 affected. He became ataxic at age 12 years and on examination at age 19 years had retinitis pigmentosa, with limited ocular fields, absence of night blindness, and normal ERG. Other features included anosmia, short fifth metacarpal and palmar ichthyosis, pes cavus, musculature weakness, and nerve hypertrophy, which was confirmed by sural nerve biopsy. His sister presented at age 20 years with postpartum ataxia and numbness in her fingers and toes. She had profound retinitis pigmentosa, abnormal ERG, anosmia, sensory and motor dysfunction with nerve hypertrophy, and mild pes cavus. The third affected sib, a brother, had mild retinitis pigmentosa and anosmia, but no other signs on screening at age 24 years. The second proband originated from a family comprising 8 sibs with 2 living affected members. Although born with bilateral cataracts, she presented to a neurology clinic at age 20 years with polyneuritis and onset of ataxia at age 19 years. She had bilateral short fifth metacarpals and metatarsals, and mild retinitis pigmentosa. Her brother presented at age 34 years with mild ataxia and mild retinitis pigmentosa but no night blindness, obvious anosmia, or deafness. Neither patient had any episodes of ichthyosis or signs of deafness. One other male sib died of supposed poliomyelitis with symptoms of weakness and ataxia at age 12 years.
In a 58-year-old patient with a phenotype indistinguishable from that of classic Refsum disease, Braverman et al. (2002) detected compound heterozygosity for a premature termination mutation (601757.0007) and a splice site mutation (601757.0008) in the PEX7 gene. A ... In a 58-year-old patient with a phenotype indistinguishable from that of classic Refsum disease, Braverman et al. (2002) detected compound heterozygosity for a premature termination mutation (601757.0007) and a splice site mutation (601757.0008) in the PEX7 gene. A patient with bilateral cataracts but with otherwise normal exams was compound heterozygous for 2 missense mutations (e.g., 601757.0002). Horn et al. (2007) provided follow-up of this patient. In 3 affected sibs with a clinical diagnosis of Refsum disease, van den Brink et al. (2003) found compound heterozygosity for 2 mutations in the PEX7 gene: Y40X (601757.0009) and a 7-bp duplication (601757.0010). Another unrelated patient was compound heterozygous for Y40X and a missense mutation (T14P; 601757.0011).