Mast Syndrome

A number sign (#) is used with this entry because Mast syndrome, also known as autosomal recessive spastic paraplegia-21 (SPG21), is caused by mutation in the gene encoding the 33-kD acidic cluster protein (ACP33; 608181) on chromosome 15q22.

Description

Mast syndrome is an autosomal recessive complicated form of hereditary spastic paraplegia in which progressive spastic paraparesis is associated in more advanced cases with cognitive decline, dementia, and other neurologic abnormalities. Symptom onset usually occurs in adulthood, and the disorder is progressive with variable severity. Brain imaging shows thinning of the corpus callosum. The disorder occurs with high frequency in the Old Order Amish (summary by Simpson et al., 2003).

For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).

Clinical Features

In an Ohio Amish isolate, Cross and McKusick (1967) found 20 cases of a recessively inherited form of presenile dementia, which they termed Mast syndrome. Onset in the late teens or twenties and slow progression with development of spastic paraparesis and basal ganglion manifestations were features.

Simpson et al. (2003) investigated 29 family members from the extended Amish pedigree originally studied by Cross and McKusick (1967), of whom 14 were affected with Mast syndrome. The condition was clearly progressive in all cases, leading to akinetic mutism in the most severely affected subjects. Developmental delays, including motor difficulties with mild incoordination and awkward running, were sometimes noted in childhood. The patients were perceived as relatively normal in teenage years and early adulthood, and several were married, had children, obtained driving licenses, and held jobs. In some, decline in walking and mental function was evident by the early twenties, whereas in others there was no clear history of a decline before their late thirties or early forties. Examination revealed pyramidal signs in all subjects, with hypertonicity, brisk reflexes, and extensor plantar responses; these were more severe in the lower than in the upper limbs. MRI showed thin corpus callosum and white matter abnormalities.

Ishiura et al. (2014) reported 2 Japanese brothers with autosomal recessive SPG21. The patients had onset of gait disturbances in their fifties and sixties, much later than that reported by Cross and McKusick (1967) and Simpson et al. (2003). The Japanese brothers had a slowly progressive disorder and walked with assistance. Features included spasticity, hyperreflexia, and weakness of the lower limbs, with the upper limbs showing only hyperreflexia. Both had cognitive decline and apraxia. The proband had evidence of callosal disconnection syndrome, manifest as ideomotor apraxia, agraphia, and constructional impairment. Brain MRI of the proband showed thin corpus callosum and frontotemporal atrophy. Nerve conduction studies in the proband showed slightly decreased amplitude in the sural nerve. Neither patient had extrapyramidal, cerebellar, or bulbar signs, which also differed from that observed in the Amish patients with this disorder.

Molecular Genetics

By linkage analysis in the Amish pedigree with Mast syndrome originally described by Cross and McKusick (1967), Simpson et al. (2003) mapped the Mast syndrome locus to a small interval of 15q22.31 encompassing 3 genes. Sequence analysis of the 3 transcripts revealed that all 14 affected patients were homozygous for a 1-bp insertion in the ACP33 gene (601insA; 608181.0001). The protein, which had been shown to localize to intracellular endosomal/trans-Golgi transportation vesicles and was thought to function in protein transport and sorting, was designated maspardin (Mast syndrome, spastic paraplegia, autosomal recessive, with dementia).

In 2 Japanese brothers with autosomal recessive spastic paraplegia-21, Ishiura et al. (2014) identified a homozygous missense mutation in the ACP33 gene (A108P; 608181.0002). Functional studies of the variant were not performed. The proband was ascertained from a larger cohort of 129 Japanese patients with spastic paraplegia who were analyzed for mutations in candidate spastic paraplegia genes.