Familial ALS With p. L127S (L126S) Variant of the Cu/Zn SOD1 Gene: A Report of Two New Cases and Literature Review

Abstract

Herein, we report two autopsy cases of familial ALS with a p. L127S (L126S) SOD1 variant. Case 1 involved a 62-year-old woman who presented with lower-extremity muscle weakness with lower motor neuron signs. The patient developed bulbar palsy and died of respiratory failure 9 years after onset. Case 2 (the second son of Case 1) presented with lower-extremity muscle weakness at the age of 38 years, with upper and lower motor neuron signs and died of respiratory failure 8 years after onset. The pathological findings in both cases predominantly consisted of lower motor neuron loss and degeneration of the lateral and posterior funiculi. Numerous conglomerate hyaline inclusions (CHIs) were observed in the remaining motor neurons. Vacuole formation was observed inside the inclusions, sometimes with granular structures. Some inclusions were positive for ubiquitin, p62, and SOD1. Electron microscopy revealed that CHIs were composed of neurofilaments and expanded mitochondria. By literature review, ALS with p. L127S disclosed a male-dominant incidence rate, a variety of ages at onset, and low penetrance. The initial symptom was exclusively lower limb weakness. One-third of the patients only showed lower motor neuron signs and half did not present with bulbar symptoms. The neuropathological findings commonly observed in ALS with p. L127S variants were mainly the degeneration of lower motor neurons and the sensory system, including the posterior column, Clarke's nucleus, and the associated cerebellar system. The formation of intracytoplasmic hyaline inclusions was also a prominent feature. ALS with p. L127S variant should be included in the possible diagnosis of slowly progressive muscle weakness in the lower extremities, with or without family history or upper motor neuron signs. The loss of lower motor neurons and the accumulation of neurofilaments in the remaining neurons are key to the pathological diagnosis for ALS with p. L127S variant.

Keywords: SOD1; familial amyotrophic lateral sclerosis; neuronal intracytoplasmic inclusion; p. L127S variant; vacuolation.

FIGURE 1

The family tree of the two cases. II‐3; Case 1, III‐3; Case 2. Numbers indicate the age during diagnosis or death (d.). P; proband.

FIGURE 2

SOD1 gene analysis from leukocytes of Case 2. A heterozygous variant from TTG to TCG in exon 5 is observed, which results in the replacement of leucine at position 127 with serine (p. L127S).

FIGURE 3

Distribution of neuronal loss and gliosis. Both patients show degeneration of the lateral and posterior columns (A and G, respectively). Neuronal loss and gliosis occur in the dorsal part of Clarke's nucleus (D and I, respectively). The dentate nucleus in Case 1 shows grumose degeneration (F). A–F, Case 1; G–I, Case 2. (A) L5 level of the spinal cord in Case 1: KB staining, scale bar = 1 mm. (B) Neuronal loss and gliosis in the anterior horn of the lumbar cord. The remaining neurons contain intraneuronal inclusions. L5, Case 1: H&E staining, scale bar = 50 μm. (C) Betz cells of the primary motor cortex of Case 1 are well preserved, with some phagocytosis (arrow). Precentral gyrus. H&E staining, scale bar = 50 μm. (D) The central gray area of the thoracic cord in Case 1 shows the depletion of the dorsal part of Clarke's nucleus. Th6, KB staining, and scale bar = 200 μm. (E) Under high magnification, severe neuronal loss and gliosis are observed in the dorsal part of Clarke's nucleus. Th6, H&E staining, and scale bar = 50 μm. (F) Grumose degeneration is observed in the dentate nucleus. Case 1: Dentate nucleus, cerebellum, H&E staining, and scale bar = 100 μm. (G) In Case 2, the degenerative tract involves the spinocerebellar tract (arrow). Case 2: L5, KB staining, and scale bar = 1 mm. (H) The anterior horn of the cervical cord shows neuronal loss and gliosis. CHIs are detected in the remaining neurons. Case 2: C8, H&E staining, and scale bar = 50 μm. (I) Severe neuronal loss in the dorsal part of Clarke's nucleus. Case 2: Th12, KB staining, and scale bar = 100 μm.

FIGURE 4

Pathological features of the neuronal intracytoplasmic inclusions of Case 1 and 2. A common feature is the presence of CHIs with vacuoles. The results of each staining are as follows. (A) A lobulated inclusion with a small vacuole in the Betz cell. Case 1: PCG, H&E staining, and scale bar = 20 μm. (B) The inclusion is not stained by Bodian stain. Case 1: PCG, scale bar = 20 μm. (C) A few inclusions are partially positive for Gallyas staining. Case 1: PCG, Gallyas staining, and scale bar = 20 μm. (D) Cranial motor neurons and dendrites containing the conglomerate hyaline inclusions. Case 2: VII motor nucleus, H&E staining, and scale bar = 20 μm. (E) Conglomerate hyaline inclusions in the cytosol and dendrites are partially positive for SOD1. Case 1: VII motor nucleus, SOD1, and scale bar = 20 μm. (F) CHIs are positive for phosphorylated neurofilaments. Case 2: Hypoglossal nucleus, SMI31, and scale bar = 20 μm. (G) Some of the inclusions are positive for ubiquitin. Case 1: PCG, scale bar = 20 μm. (H) Inclusions stained for P62. Case 1: PCG, scale bar = 20 μm.

FIGURE 5

The images that are thought to depict the progression of inclusion bodies and vacuoles formation. (A) A CHI is present in the cell body of neurons that appears normal (arrow). (B) CHIs gradually increases in volume and multiple masses coil around and compress the cell body. (C) A non‐uniform density area appears within portions of the CHI that fills the cell body. (D) In the areas of the non‐uniform density region, a very small vacuole is contained. (E) These vacuoles gradually increase in number, with some existing as fused structures. (F) When vacuoles fuse to a certain extent, the granular substances are visible in clusters. A: Case 1, C3 level anterior horn of the spinal cord. B–F: Case 2, VII motor nucleus. A–F, H&E staining and scale bar = 50 μm.

FIGURE 6

Electron microscopic examination of a CHI. An area containing only neurofilaments is present in the lower right part of the elliptical CHI. The upper two‐thirds contain enlarged mitochondria. Some of the enlarged mitochondria contain electron‐dense granular‐like structures. Scale bar = 1 μm.