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.

Abbreviations

CHIs

Conglomerate hyaline inclusions

CMAP

Compound motor action potential

FVC

Forced vital capacity

MMT

Medical Research Council Scale for Muscle Strength/manual muscle testing

MNCV

Motor nerve conduction velocity

NF

Neurofilament

PCG

Precentral gyrus

SCV

Sensory nerve conduction velocity

Uq

Ubiquitin

1. Introduction

ALS is a fatal neurodegenerative disorder that predominantly affects the upper and lower motor neurons. Approximately 5%–10% of ALS cases are familial. Genetic studies elucidated that SOD1 variants are the most common cause of familial ALS (FALS) in Japan [1] and the p. L127S (L126S) variant of SOD1 is one of the most common mutations in FALS and sporadic ALS patients [2]. Patients with the p. L127S variant in SOD1 tend to present with lower‐limb onset, slow progression, and a lower motor neuron‐driven clinical course [2, 3]. Pathologically, a few reports of ALS with the p. L127S variant of SOD1 show spinal cord degeneration with posterior column or spinocerebellar tract involvement and formation of intraneuronal inclusions [4, 5]. Now that therapeutic agents have been developed for ALS with SOD1 variants, it is important to understand the clinical course of various cases to enable early diagnosis. As the number of cases increases and pathological features are clarified, it is expected that we will gain more insight into pathophysiology and treatment. Here, we present a clinicopathological study of familial patients with ALS and a p. L127S point mutation in SOD1.

2. Case Presentation

2.1. Case 1

A 62‐year‐old Japanese woman first noticed lower‐extremity weakness and gait disturbances. The patient's symptoms were progressive, and within 2 years she required a cane to walk. At the age of 67, the patient developed muscle wasting in the upper extremities. The patient was admitted to a hospital and a neurological examination revealed quadriparesis and fasciculation, with no signs of upper motor neuron involvement. Muscle strength was mildly diminished (level 4 on the Medical Research Council Scale for Muscle Strength/manual muscle testing MMT) in the upper extremities, and her grip strength was 12 kg with her right hand and 10 kg with her left. There was mild to moderate weakness in the lower extremities (level 3–4) with hyporeflexia. The strength of the sternocleidomastoid muscle was well preserved (level 4). Routine serological biochemistry revealed a slight elevation of CK (271 U/L; normal range, 59–248 U/L). Brain and cervical MRI results were normal. Electrophysiological examination revealed denervation potentials in all limbs and paraspinal muscles, whereas the conduction velocity of the nerves was normal. The patient was clinically diagnosed with spinal muscle atrophy. At the age of 69, her muscle strength was moderately diminished (level 2–3) in the upper extremities and severely in the lower extremities (level 1–2). She occasionally choked and exhibited mild tongue atrophy. According to the spirogram, forced vital capacity (FVC) was 1277 mL (%FVC 51.1%). Nine years after onset, she developed bulbar palsy and died of respiratory failure at 71 years of age. The total disease duration was 9 years, 2 months.

2.2. Case 2

This patient was the second son of Case 1 (Figure 1). The patient was 38 years old when he noticed that he could not stand on his toes because of muscle weakness in the distal lower limbs. The patient had trouble running and ascending stairs. Six years after onset, he developed weakness in the upper extremities. A neurological examination revealed spastic quadriparesis (level 4 in the upper extremities and level 3 in the lower extremities on MMT; grip strength: right 22 kg and left 10 kg) and muscle wasting in his thenar eminences. He exhibited hyperreflexia of the upper extremities, whereas the axial and patellar tendon reflexes exhibited hyporeflexia. Hoffman reflexes were positive and plantar reflexes were bilateral extensors. Routine serological examinations revealed normal results. Cervical MRI revealed spinal canal stenosis at C3‐C5 with mild compression of the spinal cord. Electrophysiological examination revealed normal nerve conduction velocities, and needle electromyography revealed denervation potential in all limbs. According to the spirogram, FVC was 1820 mL (%FVC 52%). The patient died of respiratory failure at 46 years of age. The total disease duration was 8 years, 3 months. The clinical diagnosis was ALS.

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.

2.3. Genetic Findings

After disease onset, informed consent was obtained from Case 2, and gene analysis was performed. DNA was extracted from the patient's leukocytes, amplified by PCR, and sequenced for each SOD1 exon. This revealed a heterozygous variant from TTG to TCG in exon 5, which resulted in the replacement of leucine at position 127 with serine (p. L127S). The results of the SOD1 gene analysis for Case 2 are shown in Figure 2.

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).

3. Pathological Findings

Autopsy was performed 2 h postmortem in Case 1 and 10 h 30 min postmortem for Case 2. The brain and spinal cord were fixed with buffered 10% formalin, embedded in paraffin, and prepared for routine examination with H&E and KB stains, and Bodian's silver impregnation. Tissue samples were obtained from selected sections of the spinal cord, medulla, midbrain, cerebellum, and coronal sections of the striatum, hippocampus, thalamus, subthalamic nucleus, and cerebral cortices. Immunohistochemical staining was performed on selected sections using the following primary antibodies: anti‐human PHF‐Tau AT8 (mouse monoclonal, clone AT8 IGH135, Lot No. 253747, Cosmo Bio, Tokyo, Japan), anti‐phosphorylated transactivation response DNA‐binding protein of 43 kDa (p‐TDP‐43) (S409/S410) (mouse monoclonal, clone 11–9; Cosmo Bio, Tokyo, Japan), anti‐fusion, TLS, translocated in liposarcoma protein, pigpen, POMp75 (FUS) (HPA008784, Lot No. F91890, Sigma‐Aldrich, St. Louis, MO, USA), anti‐phosphorylated neurofilament protein (NF) (SMI31, Lot No. 17, Sternberger Monoclonals; BioLegend, San Diego, CA, USA), anti‐SOD‐1 (courtesy of Dr. Asayama, Yamanashi University, Yamanashi, Japan, 1984), anti‐p62 protein (GP62‐C/DS‐090514; PROGEN, Heidelberg, Germany), and anti‐ubiquitin (rabbit anti‐ubiquitin, Code No. Z 0458, Lot 097; DAKO, Glostrup, Denmark). Immunohistochemical staining was performed using a standard avidin‐biotin complex method (Nichirei, Tokyo, Japan) or a Ventana automated immunostaining instrument (Ventana BenchMark GX; Roche, Basel, Switzerland). For the electron microscopic examination, a small part of the anterior horn of the L5 level spinal cord fixed with 10% buffered formalin was post‐fixed with phosphate buffered 2.5% glutaraldehyde, treated with 1% osmium tetroxide, and embedded in epoxy resins according to standard procedures. Ultrathin sections stained with uranyl acetate and lead citrate were examined by a transmission electron microscope.

Macroscopically, no remarkable gross abnormalities were observed, except for atrophy of the ventral roots of the spinal cord (brain weight: 1232 g in Case 1, 1502 g in Case 2, post‐fixed).

3.1. Microscopic Findings

Case 1: Degeneration and myelin pallor were observed in the lateral and dorsal columns of the spinal cord (Figure 3A). Neuronal loss with gliosis was observed in the anterior horn cells of the spinal cord and the brainstem motor nuclei (Figure 3B). Neuronal loss in the primary cortex was mild, and phagocytosis of Betz cells was observed (Figure 3C). We found severe neuronal loss in Clarke's column (Figure 3D,E) and neuronal loss with gliosis in the dentate nucleus, with grumose degeneration (Figure 3F).

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.

Numerous intracytoplasmic conglomerate hyaline inclusions (CHIs), negative for Luxol Fast Blue, PAS, and Alcian blue staining, sometimes containing eosinophilic granules, were found in the spinal anterior horn cells, neurons of the brainstem reticular formation, brainstem motor nuclei (VII, X, XII), accessory cuneatus nuclei, and large pyramidal neurons (Betz cells) of the precentral gyrus (Figure 4A). CHIs were negative on Bodian staining (Figure 4B), and a few were positive on Gallyas staining (Figure 4C).

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.

Case 2: Microscopic examination revealed moderate‐to‐severe depletion of the lower motor neurons in the spinal cord and brainstem associated with mild myelin pallor of the pyramidal tract, posterior column, and spinocerebellar tracts (Figure 3G). Neuronal loss in the primary cortex was observed. In the remaining neurons, many CHIs were observed in the spinal anterior horn cells, the neurons of the brainstem reticular formation, and the cranial motor nuclei (Figures 3H and 4D). The dorsal part of Clarke's nucleus was depleted, as in Case 1 (Figure 3I).

Immunohistochemistry revealed that some inclusions around the vacuoles were positive for SOD1 (Figure 4E), ubiquitin (Figure 4G), and p62 (Figure 4H). The fibrillar components of CHIs were stained with SMI31 (Figure 4F). In observations regarding the relationship between CHIs and vacuoles, some neurons contain inclusions only with CHI (Figure 5A,B), some have a small vacuole in the CHI (Figure 5C). Some of the vacuoles in the inclusions appeared to have gradually fused together in large numbers (Figure 5D,E). Granular substances are visible as dots within individual vacuoles. However, when vacuoles fuse to a certain extent, the granular substances are visible in clusters (Figure 5D–F).

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.

The Bunina body was not found in either case, and no positive p‐TDP‐43 and FUS inclusions were observed in the remaining motor neurons. Senile plaques, neurofibrillary tangles, and astrocytic tau accumulations were not observed.

Electron microscopy revealed that the intraneuronal inclusions consisted of NFs and expanding mitochondria (Figure 6).

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.

4. Discussion

4.1. Clinical Features of p. L127S SOD1 Mutation

The present study demonstrated that cases of FALS with the p. L127S SOD1 mutation showed symptom onset in the lower limbs. No sensory disturbances were detected during the clinical course in either patient. The duration of the disease was relatively long (9 years, 2 months; 8 years, 3 months).

Twelve patients from five families and three sporadic cases with the p. L127S mutation have been reported in the Japanese literature [5, 6, 7]. Table 1 shows the clinical characteristics of the p. L127S cases. A male‐dominant incidence rate (M:F 12:3), a variety of ages at onset (28–79 years), and low penetrance (asymptomatic cases over 80 years, sporadic cases) were observed. The initial symptoms in these patients were lower limb weakness and gait disturbance. A few patients showed numbness or sensory disturbances at onset. Disease duration varied between 2 and over 13 years, with two‐thirds of cases demonstrating a disease duration of more than 5 years. One‐third of the patients only showed lower motor neuron signs and half did not present with bulbar symptoms. Recently, patients with ALS and peripheral nerve disorders were reported to present with a high prevalence of SOD1 variants, including p. L127S [7]. As for p. L127S, sensory abnormalities were less frequent, and abnormalities of nerve conduction velocities were only present in a small number of patients and to a lesser degree.

TABLE 1.

Clinical findings of ALS with p. L127S (L126S) variant.

References	Murakami T.			Takehisa Y.				Iwashima T.		Hideshima M.	Ando M.			Present cases
Published	2001			2001				2010		2020	2025
Family	A			B		C		D		Sporadic	E	Sporadic	Sporadic	F
Case	1	2	Mother of 1 and 2	3	4	5	6	7	8	9	10	11	12	13 (case 1)	14 (case 2)
Sex	M	M	F	M	M	M	F	M	M	M	F	M	M	F	M
Age at onset (years)	52	42	over 80 years	52	28	74	54	79	76	69	33	43	70	62	38
Age at death (years)	alive at 56 y.o.	alive at 52 y.o.	N.A.	58	36	76	68	83	Alive at 79 y.o.	75	Alive at 36 y.o.	Alive at 56 y.o.	Alive at 77 y.o.	71	46
Disease duration (years)	> 5	> 10	N.A.	6	8	2	14	4	> 3	6	> 3	> 13	> 7	9	9
Duration from onset to NPPV/TIV (years)	−	−	N.A.	6	−	−	−	−	N.A.	6	N.D.	N.D.	N.D.	−	−
Duration from onset to PEG	−	−	N.A.	−	−	−	−	−	N.A.	N.A.	N.A.	N.D.	N.A.	−	−
Spinal canal stenosis	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	C3‐5, L5‐S1	C3‐7, L2‐5	−	N.D.	N.D.	N.D.	−	C3‐5
Initial symptom	Weakness of the lower extremities	Weakness of the lower extremities	Asymptomatic	Weakness of the left lower extremities	Weakness of the right lower extremities	Weakness of the lower extremities	Weakness of the lower extremities	Numbness of the right leg	gait disturbance, weakness of the lower extremities	Weakness of the left lower extremities	Gait disturbance	Weakness of the left lower extremities	Weakness of the left lower extremities, sensory disturbance	Gait disturbance, weakness of the lower extremities	Gait disturbance
Weakness: lower extremities	+	+	−	+	+	+	+	+	+	+	+	+	+	+	+
Weakness: upper extremities	−	−	−	+	+	+	+	+	+	+	+	−	+	+	+
Pyramidal sign	+	N.D.	N.D.	−	−	−	−	−	+	−	+	−	−	−	+
Bulbar sign	−	−	−	+	N.D.	+	N.D.	−	−	−	−	−	−	+	+
MNCV findings	Within normal rage	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	Tibial and peroneal CMAP not evoked, normal SCV	Tibial and peroneal low CMAP, normal SCV	N.D.	Within normal rage a	Tibial CMAP 0.2 mV, Sural SNAP 4.8μV a	Tibial MNCV 37 m/s, Tibial CMAP 0.5mV a	Within normal rage	Within normal rage

Abbreviations: ALS, amyotrophic lateral sclerosis; CMAP, compound motor action potential; MNCV, motor nerve conduction velocity; N.A., not applicable; N.D., not described; NPPV, noninvasive positive pressure ventilation; SCV, sensory nerve conduction velocity; TIV, tracheal intermittent ventilation.

^a Normal range: Tibial CMAP > 4.4 mV, Tibial MNCV > 41.7 m/s, Sural SNAP > 5.0 μV, in this paper.

4.2. Neuropathological Features of p. L127S

4.2.1. Neuronal Degeneration of Motor Neurons

Microscopic examination of Cases 1 and 2 revealed depletion of lower motor neurons in the spinal cord and brainstem, associated with mild degeneration of the pyramidal tract and posterior column. Mild neuronal loss was observed in the primary motor cortex. These findings are like those of previous reports [3, 4].

4.2.2. Other Degenerative Lesions

Previous reports have shown other common features such as lesions of the gracile fasciculus and Clarke's column, as well as involvement of part of the cerebellar system (Table 2). The gracile fasciculus contains long ascending branches derived from the dorsal roots of the sacral, lumbar, and lower thoracic spinal cord. The dorsal part of Clarke's nucleus is in the C8 to L2 level gray matter of the spinal cord. The lateral branches of the afferent fibers from the dorsal root ganglion synapse with neurons in the nucleus. The efferent fibers of this nucleus form the posterior spinocerebellar tract [8]. The accessory cuneate nucleus also sends cuneocerebellar fibers to the cerebellum. These fibers reach the anterior lobe of the cerebellar cortices. In contrast, the afferent fibers of the dentate nucleus originate mainly from the cerebellar cortices and other projections from the pontine nuclei, inferior olivary nucleus, and reticular nucleus capitis. Clinically detectable or not, a disturbance of the sensory system occurs in the central nervous system of the patients with the p. L127S variant, which may result in pathologically detectable posterior column degeneration, and secondarily, abnormalities in the conduction pathways of the sensory relay, including the cerebellar system. In Case 1, the neurons of these groups of nuclei demonstrated inclusions, as seen in motor neurons, but the number of inclusions and the affected number of neurons were small, and SOD1 immunostaining was negative.

TABLE 2.

Pathological findings of ALS with p. L127S (L126S) variant.

References		Takehisa Y.	Hideshima M.	Case 1	Case 2
Case number from Table 1		3	9	13	14
Brain weight (g)		N.M.	1234	1232	1502
Loss of Betz cells		N.M.	N.M.	+	+, mild
Loss of motor nuclei in the brainstem		+	N.M.	+	+
Loss of motor neurons in the anterior horn of the spinal cord		+	+	+	+
Other degenerative nuclei	Clarke's column	+	+	+	+
	Other	Dentate nucleus	Inferior olivary nuclei	Dentate nucleus	−
Degeneration of pyramidal tract		+	+, minimal	+	+
Other degenerative tracts	Middle zone of the posterior column (Fasciculus gracilis)	+	+	+	+
	Spinocerebellar tracts	+	+	−	+
	Pontine transverse fibers	+	−	−	−
Neuronal cytoplasmic inclusions	Primary motor cortex	N.M.	+	+	N.D.
	Cranial motor nuclei	+	+	+	+
	Anterior horn of the spinal cord	+	+	+	+
	Other nuclei	Dentate nucleus	−	Accessory cuneate nucleus	−
Inclusions labeled by immunohistochemistry		Uq, SOD1, NF	SOD1, NF	Uq, p62, SOD1, NF	Uq, p62, SOD1, NF

Abbreviations: N.D., not described; N.M., not measured; NF, neurofilaments; SOD1, superoxide dismutase 1; Uq, ubiquitin.

4.2.3. Features of Inclusions

The present cases showed numerous intracytoplasmic CHIs in motor neurons. The inclusions often contained fibrillary structures and vacuoles. Immunohistochemically, CHIs were positive for SMI31 and partially positive for ubiquitin, p62, and SOD1 antibodies. Some vacuoles contained granules that were positive for ubiquitin and SOD1. By electron microscopy, the inclusion showed a loose distribution of NFs and expanding mitochondria. This electron microscopy image was remarkably like the enlarged axon appearance in the anterior horn of ALS reported by Oyanagi [9] and was considered to exhibit a structure like that of axonal spheroids. SOD1‐positive granules may be intracellular organelles entrapped in NFs.

4.2.4. Vacuolar Formation

In our cases, vacuoles were observed in the intra‐inclusion space or in the cytosol of the motor neurons. Inclusions without vacuoles were also present in the neurons; however, no vacuoles without inclusions were found. It appears that vacuoles form within CHI, gradually fusing and expanding. Based on these findings, we suggest that CHI formation precedes vacuole formation. In transgenic mice expressing mutant SOD1, pathological investigations revealed vacuoles [10, 11]. In G93A mice, electron microscopy revealed widespread mitochondria‐derived vacuoles [12]. Vacuoles are composed of expanded mitochondrial intermembrane space and contain peroxisomes and SOD1 aggregates. Higgins, Jung, and Xu suggested that mutant SOD1 aggregation causes mitochondrial degeneration by inducing extension and leakage of the outer mitochondrial membrane, and expansion of the intermembrane space. Despite the limitations in evaluating the pathology of mice with a high‐copy SOD1 aberrant gene inserted in the same manner as that of humans, it is conceivable that mitochondrial abnormalities may be implicated in the formation of vacuoles.

In conclusion, the clinical features of FALS with p. L127S include a predominance of the onset of symptoms in the lower limbs. Pathologically, the main lesion was in the lower motor neurons, with mild involvement of the upper motor neurons. Some cases involve parts of the sensory or cerebellar systems. The formation of intracytoplasmic hyaline inclusions, which electron microscopically resemble spheroids in the remaining motor neurons, was also a prominent feature. ALS with the p. L127S variant should be included in the possible diagnosis of slowly progressive muscle weakness in the lower extremities, with or without a 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 the p. L127S variant.

Ethics Statement

The study was approved by the Ethics Committee of the National Hospital Organization of Osaka Toneyama Medical Center (TNH‐R‐2022023‐2).

Consent

Informed consent was obtained from the patients described in this case report.

Conflicts of Interest

The authors declare no conflicts of interest.

Inoue K., Toyooka K., Fujimura H., et al., “Familial ALS With p. L127S (L126S) Variant of the Cu/Zn SOD1 Gene: A Report of Two New Cases and Literature Review,” Neuropathology 45, no. 6 (2025): e70028, 10.1111/neup.70028.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.