A novel mutation in ALS2 associated with severe and progressive infantile onset of spastic paralysis

Abstract

Infantile onset ascending spastic paralysis (IAHSP) is a type of recessively inherited spastic paraplegia. We investigated the clinical and genetic cause of a recessively inherited disorder in two siblings manifesting severe spasticity in the lower limbs which hindered their gait. A novel homozygous nonsense mutation c.1918 C > T (p.Arg640*) was identified after whole-exome sequencing within ALS2 in the DNA of both patients. The obligate carriers were heterozygous for the mutation and other unaffected members were homozygous for the wild type allele. The variant was absent from 100 control chromosomes and all public databases. This report extends the allelic heterogeneity of ALS2 mutations and emphasizes the importance of genetic testing for diagnosis of pediatric disorders.

Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant

“…At least 22 of the reported ALS2 pathogenic variants have been associated with IAHSP and have been described in a total of 42 individuals. The majority of reported cases originate from the Middle East and Mediterranean countries [2][3][4][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Table 2 provides a summary of the mutations and clinical features of the previously reported IAHSP cases.…”

Altered oligomeric states in pathogenic ALS2 variants associated with juvenile motor neuron diseases cause loss of ALS2-mediated endosomal function

“…C, relative abundance of HMW, tetra-octameric, and dimeric ALS2-RLD complex. Values of the HMW (fraction 1-8), tetra-octameric form (fraction no.9 -16), and dimeric form (fraction no [17][18][19][20][21][22][23]. are expressed as mean (Ϯ S.D.)…”

ALS2-related disorders in Spanish children

“…3 Disposition of the ALS2 mutations identified in the Spanish children (in bold) and some other patients throughout the alsin sequence. Mutations G49R and R640X had previously been described in AIHSP patients 16,19 . IAHSP, infantile ascending hereditary spastic paraplegia; JALS, juvenile amyotrophic lateral sclerosis; JPLS, juvenile primary lateral sclerosis; RCC1, regulator of chromatin condensation 1; DH/PH, Dbl and Pleckstrin homology; MORN: membrane occupation and recognition nexus; VPS9, vacuolar protein sorting 9 made.…”

“…1 and 2 with the available clinical data of the patients as well as in Fig. 3 to show its location in the alsin sequence together with many of the ALS2 mutations described from 2001 to 2018 [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”

“…F2 patient would be a typical IAHSP case due to a compound heterozygous ALS2 genotype of two previously reported mutations, R640X, of paternal derivation, and G49R, maternal. The nonsense R640X mutation that lies in a sequence between RCC1 and DH domains has been found in homozygosis in two Pakistani siblings considered IAHSP cases [19]. On the other hand, the missense mutation G49R located upstream of RCC1 domain has also been described as part of a compound heterozygous ALS2 genotype, together with mutation G477AfsX19 in a boy described as first Portuguese IAHSP case [16].…”