Spastic Paraplegia 23, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that spastic paraplegia-23 (SPG23) is caused by homozygous mutation in the DSTYK gene (612666) on chromosome 1q32.

Description

Spastic paraplegia-23 is an autosomal recessive neurologic disorder characterized by childhood-onset spastic paraplegia resulting in gait difficulties and associated with pigmentary abnormalities, including premature graying of the hair and vitiligo-like or hyperpigmented skin lesions. Some patients may also have a peripheral neuropathy (summary by Lee et al., 2017).

Clinical Features

Abdallat et al. (1980) and Lison et al. (1981) reported a consanguineous Jordanian family in which 2 brothers and a sister from first-cousin parents had progressive spastic paraparesis and peripheral neuropathy, as well as disordered skin and hair pigmentation, including vitiligo, hyperpigmentation, numerous lentigines, and premature graying of body hair. Sural nerve biopsy showed axonal degeneration; skin biopsy showed abnormal epidermal pigmentation. The proband had diffusely depigmented hair and skin at birth. From the age of 6 months, patchy pigmentation developed, especially in exposed areas of the skin, and his hair developed irregular pigmentation. Progressive paraparesis was first noted at age 6 years. The face was thin with 'sharp' features. The syndrome was considered to be autosomal recessive.

Stewart et al. (1981) described 2 sisters and a brother and 2 daughters of 1 of the affected sisters who had spastic paraplegia, peroneal neuropathy and crural hypopigmentation mainly about the knees and in the upper pretibial area. Daras et al. (1983) described 2 brothers and a sister from first-cousin parents who had progressive spastic paraplegia and cerebellar ataxia together with large hyperpigmented nevi on the legs.

In an inbred Arab family in Israel, Mukamel et al. (1985) observed 4 affected sibs. All 4 sibs had severe incapacitating spastic paraparesis from early childhood, combined with abnormalities of skin and hair pigmentation. Two other sibs with similar dermatologic findings died at the ages of 3 and 4 months of sepsis. The proband, a 13-year-old boy, had microcephaly, canities, many cafe-au-lait spots and freckles all over his body, and spastic paraplegia. White hair was present from birth. Blumen et al. (2003) presented follow-up information on the family reported by Mukamel et al. (1985). The 4 affected sibs ranged in age from 22 to 32 years, and all had a prematurely aged facial appearance, with white scalp from birth and premature graying of eyebrows and eyelashes. Skin was hypopigmented in covered areas, with patchy, vitiligo-like depigmentation in sun-exposed areas. All affected sibs had severe weakness and spasticity of the lower extremities and mild cognitive impairment.

Bamforth (2003) described an 18-year-old girl of northern European ancestry with acquired hypopigmentation and neurologic abnormalities. Her parents were not consanguineous and had 4 other healthy children. The patient's features included vitiligo, diffuse lentigines, increased deep tendon reflexes, spastic gait, kyphoscoliosis, small stature, and normal intelligence. Mode of inheritance was not clear.

Lee et al. (2017) reported 2 unrelated families with SPG23, including 4 individuals from a consanguineous family of Kuwaiti-Jordanian descent and 2 sisters from a consanguineous Israeli family. The 23-year-old proband in the first family was described in detail. He had onset of waddling gait around age 2 to 3 years followed by spastic paraplegia; he was wheelchair-bound from age 9. He had premature graying of the hair and vitiligo-like skin lesions, as well as a horseshoe kidney detected on imaging; brain imaging showed no abnormalities. He had normal intelligence and no evidence of epilepsy or sensory impairment, but he and his younger affected brother both had bowel urgency and incontinence. The younger brother had febrile convulsions at age 6 and no urogenital anomalies. Two Israeli sisters had spastic paraparesis with hyperreflexia and extensor plantar responses, premature graying of the hair, vitiligo-like and pigmented skin lesions, and flexion contractures of the toes.

Inheritance

The transmission pattern of SPG23 in the families reported by Lee et al. (2017) was consistent with autosomal recessive inheritance.

Mapping

In an inbred affected Arab family first reported by Mukamel et al. (1985), Blumen et al. (2003) found linkage of the disorder to a 25-cM region on chromosome 1q24-q32 (maximum lod score of 3.05 near marker D1S2692). Haplotype analysis showed allele homozygosity in all affected members.

Molecular Genetics

In affected members of 3 unrelated families of Middle Eastern descent with SPG23, including the family reported by Mukamel et al. (1985) and Blumen et al. (2003), Lee et al. (2017) identified a homozygous intragenic deletion/insertion in the DSTYK gene (612666.0005). The deletion, which was found by a combination of whole-exome sequencing, homozygosity analysis, and copy number variation analysis in the first family, segregated with the disorder in all 3 families. Haplotype analysis indicated a founder effect. Skin biopsy from 1 of the patients showed markedly decreased immunolabeling for DSTYK compared to controls, consistent with a loss-of-function effect. Transmission electron microscopy showed focal loss of melanocytes with some remaining melanocytes showing ultrastructural features of swollen mitochondria with abnormal cristae and cytoplasmic vacuoles. Other cell types also showed these changes, findings that were consistent with increased susceptibility to stress and cell death. Patient cells and mouse fibroblasts with siRNA-mediated knockdown of Dstyk showed increased signs of apoptosis and cell death after UV exposure compared to controls.