Polyneuropathy, Hearing Loss, Ataxia, Retinitis Pigmentosa, And Cataract

A number sign (#) is used with this entry because polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is caused by homozygous or compound heterozygous mutation in the ABHD12 gene (613599) on chromosome 20p11.

Clinical Features

Fiskerstrand et al. (2009) reported a consanguineous Norwegian family in which 3 individuals had a slowly progressive neurologic disorder resembling the clinical features of Refsum disease (266500). The authors suggested naming the disorder PHARC, an acronym that describes the major features of the disorder. Features in childhood included pes cavus and Achilles tendon contractures; 1 had poor hearing in childhood. Hearing loss and visual problems related to cataracts developed in the third decade. Two patients had evidence of retinitis pigmentosa, whereas the third had borderline normal electroretinogram results. All patients developed ataxic and/or spastic gait disturbances with a progressive sensorimotor peripheral neuropathy. Other features included hyporeflexia, hyperreflexia, extensor plantar responses, and neurogenic changes on EMG. Nerve conduction velocities were decreased, indicating a demyelinating neuropathy. MRI showed minor cerebellar atrophy in 1 patient. Cognition was not affected. Biochemical studies showed normal serum phytanic and pristanic acid levels, as well as normal alpha-oxidation enzymatic activity, thus excluding Refsum disease. The family originated from a small island community, and genealogic studies showed that both sets of parents were descendants of a man born in 1585.

Fiskerstrand et al. (2010) reported 19 persons from 9 families from Norway, United Arab Emirates, United States, and Algeria, with PHARC. The phenotype in general was slowly progressive, with symptom recognition in the teens, and full expression apparent only in adulthood. The Norwegian patients tended to have onset of peripheral neuropathy in adulthood, although many had pes cavus, decreased sensation, and sensorineural hearing loss from childhood. Hearing loss occurred in childhood or teenage years in 4 and in the third or fourth decade in 4. Retinitis pigmentosa and cataracts developed in adulthood. Frank ataxia was variable and also showed a later onset. In the Emirati family, 2 patients were in their twenties, and 1 was age 6 years. Common features included absent tendon reflexes, hearing loss, ataxia, cataracts; and hearing loss occurred in childhood in all 3. Only the older 2 patients had retinitis pigmentosa. There were 7 affected individuals from 4 Algerian families. The patients ranged in age from 10 to 44 years. The older individuals were more severely affected. All patients had some evidence of a polyneuropathy, with hyporeflexia, pes cavus, and/or sensory loss, and most had gait ataxia with onset in the childhood. Four of the older patients had hearing loss, but only 1 had retinitis pigmentosa and cataract. Other common features included extensor plantar responses and cerebellar atrophy. A 50-year-old woman from the U.S., who was of French Canadian origin, developed sensorineural hearing loss at age 17 years, ataxia and dysarthria at 18, and retinitis pigmentosa and cataracts in her twenties. She had pes cavus and hammertoes, and a mild peripheral neuropathy at when examined at age 34 years. She had myoclonic seizures, but cognition was not affected, and the disease showed a slowly progressive course. None of the patients had deficits of cerebral cortical function, although 1 Algerian patient was mentally retarded.

Clinical Variability

Nishiguchi et al. (2014) studied 3 families with mutations in the ABHD12 gene (see MOLECULAR GENETICS) in which the initial diagnosis was nonsyndromic autosomal recessive retinitis pigmentosa (RP; see 268000). All affected individuals were symptom-free in the first 2 decades of life and presented with night blindness followed by central visual field loss and reduction of visual acuity; posterior subcapsular cataract was also observed in all of the patients. One proband was a 34-year-old Dutch man who did not report any neurologic symptoms but in whom a detailed examination revealed a wide-based gait, peripheral sensitivity loss in the lower extremities, and decreased tendon reflexes. Signs of ataxia included stuttering speech, an ataxic heel-knee sign, and intentional tremor with the finger-to-nose test. Audiography revealed significantly decreased sensitivity to frequencies higher than 1500 Hz to levels of 40 dB or lower in both ears. Another proband, a 38-year-old Spanish woman, was found to have bilateral hearing loss; in addition, electroneurographic study was consistent with a moderate demyelinating sensorimotor polyneuropathy in the upper and lower limbs, and MRI revealed cerebral and cerebellar atrophy. In the third family, 4 Spanish sibs ranging in age from 66 to 78 years had RP, posterior subcapsular cataract, and sensorineural hearing loss. However, examination revealed no polyneuropathy or ataxia, and their sensorineural hearing loss and cataract were attributed to either age or the normal course of RP. Nishiguchi et al. (2014) suggested that this family expanded the spectrum of phenotypes associated with ABHD12 mutations to include a nonsyndromic form of retinal degeneration.

Mapping

By homozygosity mapping of a consanguineous Norwegian family with PHARC, followed by linkage analysis and fine mapping, Fiskerstrand et al. (2009) identified a 15.96-Mb (9.88-cM) region on chromosome 20p11.21-q12 between D20S477 and D20S107, containing approximately 200 genes (maximum lod score of 6.33). Sequencing of 23 candidate genes failed to demonstrate detrimental sequence variants.

Inheritance

The transmission pattern of PHARC in the Norwegian family reported by Fiskerstrand et al. (2009) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 19 persons from 9 families from Norway, United Arab Emirates, United States, and Algeria, with PHARC, Fiskerstrand et al. (2010) identified 4 different homozygous loss-of-function mutations in the ABHD12 gene (613599.0001-613599.0004). Common mutations were found in families from Norway (613599.0001) and Algeria (613599.0003). All the mutations were predicted to result in complete loss of enzyme function. None of the patients had behavioral disturbances or appetite abnormalities potentially related to increased levels of the endocannabinoid, arachidonoyl glycerol (2-AG). The findings indicated that ABHD12 performs essential functions in the central and peripheral nervous systems and the eye. Fiskerstrand et al. (2010) noted that future drug-mediated interference with this enzyme to treat neurodegenerative diseases must consider the potential risk of long-term effects.

In a 38-year-old Spanish woman and a 34-year-old Dutch man who were initially believed to have nonsyndromic retinitis pigmentosa, Nishiguchi et al. (2014) identified homozygosity and compound heterozygosity, respectively, for mutations in the ABHD12 gene (613599.0005-613599.0007). Detailed examination of the 2 patients revealed that both had hearing loss and neurologic abnormalities, including sensorimotor polyneuropathy. In a Spanish family in which 4 sibs had retinitis pigmentosa, posterior subcapsular cataract, and sensorineural hearing loss, and were negative for known mutations associated with autosomal recessive RP, Nishiguchi et al. (2014) identified compound heterozygosity for a 1-bp deletion and a missense mutation in the ABHD12 gene. No signs of polyneuropathy or ataxia were detected in the 4 affected sibs, and their sensorineural hearing loss and cataract were attributed to either age or the normal course of RP. Nishiguchi et al. (2014) therefore suggested that this family expanded the spectrum of phenotypes associated with ABHD12 mutations to include a nonsyndromic form of retinal degeneration.