Mast Syndrome is an autosomal recessive, complicated form of hereditary spastic paraplegia with dementia. Subtle childhood abnormalities may be present, but the main features develop in early adulthood. The disease is slowly progressive, and cerebellar and extrapyramidal signs are also found in patients with advanced disease. Maspardin-ACP33-SPG21 is mutated in Mast syndrome (Cross and McKusick 1967, Simpson et al 2003); 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. A 1-bp insertion (601insA) in the ACP33 gene, causing a frameshift and premature termination of the protein.. 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) The mutation was A108P substitution
Background: Mast syndrome is a rare disorder belonging to the group of hereditary spastic paraplegias (HSPs). It is caused by bi-allelic mutations in the ACP33 gene, and is originally described in Old Order Amish. Outside this population, only one Japanese and one Italian family have been reported. Herein, we describe five subjects from the first three SPG21 families of German and Austrian descent.
Methods: Five subjects with complicated HSP were referred to our centers. The workup consisted of neurological examination, neurophysiological and neuropsychological assessments, MRI, and genetic testing.
Results: Onset varied from child- to adulthood. All patients exhibited predominant spastic para- or tetraparesis with positive pyramidal signs, pronounced cognitive impairment, ataxia, and extrapyramidal signs. Neurophysiological workup showed abnormal motor and sensory evoked potentials in all the patients. Sensorimotor axonal neuropathy was present in one patient. Imaging exhibited thin corpus callosum and global brain atrophy. Genetic testing revealed one heterozygous compound and two homozygous mutations in the ACP33 gene.
Conclusion: Herein, we report the first three Austrian and two German patients with SPG21, presenting a detailed description of their clinical phenotype and disease course. Our report adds to the knowledge of this extremely rare disorder, and highlights that SPG21 must also be considered in the differential diagnosis of complicated HSP outside the Amish community.
Title: Identification of a large homozygous SPG21 deletion in a Chinese patient with Mast syndrome Xue YY, Huang XR, Dong HL, Wu ZY, Li HF Ref: CNS Neurosci Ther, :, 2021 : PubMed
A 37-year old man presented a slight delay in early developmental milestones, cognitive decline, difficulty walking, cerebellar signs and extrapyramidal signs. Brain magnetic resonance imaging (MRI) showed a thin corpus callosum, cerebral atrophy, non-specific white-matter hyperintensity, and cerebellar atrophy. The genetic test revealed a putative homozygous deletion in SPG21 from exon 3 through exon 7, which was further validated by long-range primer-walking PCR. This is the first report of Chinese patient with Mast syndrome carrying a large homozygous SPG21 deletion.
Hereditary spastic paraplegia (HSP) is one of the most genetically heterogeneous neurodegenerative disorders characterized by progressive spasticity and pyramidal weakness of lower limbs. Because >30 causative genes have been identified, screening of multiple genes is required for establishing molecular diagnosis of individual patients with HSP. To elucidate molecular epidemiology of HSP in the Japanese population, we have conducted mutational analyses of 16 causative genes of HSP (L1CAM, PLP1, ATL1, SPAST, CYP7B1, NIPA1, SPG7, KIAA0196, KIF5A, HSPD1, BSCL2, SPG11, SPG20, SPG21, REEP1 and ZFYVE27) using resequencing microarrays, array-based comparative genomic hybridization and Sanger sequencing. The mutational analysis of 129 Japanese patients revealed 49 mutations in 46 patients, 32 of which were novel. Molecular diagnosis was accomplished for 67.3% (33/49) of autosomal dominant HSP patients. Even among sporadic HSP patients, mutations were identified in 11.1% (7/63) of them. The present study elucidated the molecular epidemiology of HSP in the Japanese population and further broadened the mutational and clinical spectra of HSP.
Mast syndrome is an autosomal recessive, complicated form of hereditary spastic paraplegia with dementia that is present at high frequency among the Old Order Amish. Subtle childhood abnormalities may be present, but the main features develop in early adulthood. The disease is slowly progressive, and cerebellar and extrapyramidal signs are also found in patients with advanced disease. Patients have a thin corpus callosum and white-matter abnormalities, as seen on magnetic resonance imaging. Using an extensive Amish pedigree, we have mapped the Mast syndrome locus (SPG21) to a small interval of chromosome 15q22.31 that encompasses just three genes. Sequence analysis of the three transcripts revealed that all 14 affected cases were homozygous for a single base-pair insertion (601insA) in the acid-cluster protein of 33 kDa (ACP33) gene. This frameshift results in the premature termination (fs201-212X213) of the encoded product, which is designated "maspardin" (Mast syndrome, spastic paraplegia, autosomal recessive with dementia), and has been shown elsewhere to localize to intracellular endosomal/trans-Golgi transportation vesicles and may function in protein transport and sorting.
Title: Mast syndrome: a recessively inherited form of presenile dementia with motor disturbances Cross HE Ref: Birth Defects Orig Artic Ser, 7:214, 1971 : PubMed
Title: The mast syndrome. A recessively inherited form of presenile dementia with motor disturbances Cross HE, McKusick VA Ref: Archives of Neurology, 16:1, 1967 : PubMed
