A number sign (#) is used with this entry because of evidence that autosomal recessive juvenile amyotrophic lateral sclerosis-5 (ALS5) is caused by homozygous or compound heterozygous mutation in the spatacsin gene (SPG11; 610844) on chromosome 15q21.

Biallelic mutation in the SPG11 gene can also cause autosomal recessive hereditary spastic paraplegia-11 (SPG11; 604360) and autosomal recessive axonal Charcot-Marie-Tooth type 2X (CMT2X; 616668), different neurodegenerative disorders with overlapping features.

Autosomal recessive juvenile amyotrophic lateral sclerosis-5 (ALS5) is a neurodegenerative disorder characterized by onset of upper and lower motor neuron signs before age 25. Affected individuals have progressive spasticity of limb and facial muscles associated with distal amyotrophy. The disorder is slowly progressive, with cases of prolonged survival of more than 3 decades (summary by Orlacchio et al., 2010).

For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).

Hentati et al. (1998) reported 22 patients with ALS from 7 families; 4 were Tunisian (9926, 9927, 9929, and 9590), 2 were Pakistani (9658 and 9729), and 1 was German (9646). The patients from Tunisia and Pakistan presented at ages ranging from 8 to 18 years with difficulty in walking and with weakness. The disease was slowly progressive. In the German family, symptoms manifested before the age of 10 years in 1 patient and at 18 years in his brother and the disease was rapidly progressive.

Orlacchio et al. (2010) reported 23 patients from 10 consanguineous families with ALS5. The families had various ethnic backgrounds, including Italian, Turkish, Brazilian, Japanese, and Canadian. Affected subjects had a slowly progressive motor neuronopathy with upper and lower motoneuron dysfunction. The mean age at onset was 16.3 years (range 7 to 23), and the mean disease duration was 34.3 years. Patients had distal muscle weakness and atrophy associated with pyramidal signs, including hyperreflexia, extensor plantar responses, and spastic gait. Some patients had mild upper and lower motoneuron symptoms, whereas others were more severely affected and wheelchair-bound with no functional hand use by the fifth or sixth decades. Most patients had pontobulbar signs, including jaw spasticity, increased facial reflexes, poor palatal elevation, weak masseter and/or pterygoids, and tongue weakness. Other features included Hoffman sign and muscle atrophy with fasciculations. EMG showed chronic neurogenic changes with fibrillation and fasciculation, and motor conduction studies showed reduced amplitudes of compound motor action potentials; sensory studies were normal. None of the patients had cognitive impairment or thin corpus callosum. Postmortem examination of 1 patient showed typical pathologic features of ALS, including small pyramids, loss of anterior horn large motor neurons and loss of large myelinated fibers in the anterolateral columns. Remaining neurons showed central chromatolysis, pigmentary degeneration, and round hyaline inclusions; Bunina bodies were not observed.

The pedigree pattern in 7 families with ALS reported by Hentati et al. (1998) was consistent with autosomal recessive inheritance.

In 4 of 7 families with ALS that did not show linkage to previously identified ALS loci on chromosomes 2q33, 21q21 and 5q13, Hentati et al. (1998) found linkage to markers in the 15q15.1-q21.1 region. Negative lod scores were encountered in 3 of the families, 1 from Tunisia and 2 from Pakistan.

In affected members of 10 unrelated families with a protracted course of autosomal recessive juvenile-onset ALS5, Orlacchio et al. (2010) identified homozygous or compound heterozygous mutations in the SPG11 gene (see, e.g., 610844.0003-610844.0004, 610844.0010-610844.0013). Most of the mutations resulted in a truncated protein, and all but 1 of the 12 different mutations identified had previously been reported in patients with spastic paraplegia-11 (604360). However, the patients reported by Orlacchio et al. (2010) had a slightly different phenotype more consistent with ALS than SPG. Functional studies of the variants and studies of patient cells were not performed. The 10 families with ALS5 were ascertained from a cohort of 25 families who underwent SPG11 gene sequencing, thus accounting for 40% of families. Orlacchio et al. (2010) did not speculate on why the same mutations led to a slightly different phenotype more consistent with ALS than SPG, but noted that the common finding of axonal involvement in both ALS and SPG suggested a common pathologic pathway in both disorders. The findings expanded the phenotype associated with SPG11 gene mutations to included autosomal recessive juvenile ALS with long-term survival.

Cox et al. (2001) sequenced the TMOD2 gene (602928), which is located on chromosome 15q21, in 2 patients and controls from a family with ALS5 and did not detect any mutations.