Additional Investigation After the Muscle Biopsy Diagnosis

Based on our interpretation of the muscle biopsy abnormalities and a positive family history of ALS, we ordered the Cu/Zn superoxidase dismutase 1 (SOD1) gene test, which showed a heterozygous in-frame deletion of GAA at the nucleotide position 481–483, resulting in Glu133del. This is a known mutation causing familial ALS (FALS), which has been reported previously [1] and listed in the ALSOD database (http://​alsod.​iop.​kcl.​ac.​uk).

Final Diagnosis

Familial ALS Caused by an SOD1 Mutation

Patient Follow-up

The patient was referred to our motor neuron disease clinic for multidisciplinary care. His weakness slowly and continuously progressed over the course of 2 years. He also developed weakness in the upper limbs and respiratory muscles with supine breathing difficulty.

Discussion

ALS, also known as Lou Gehrig’s disease , is a degenerative motor neuron disease that affects both upper motor neurons in the motor cortex and lower motor neurons in the brainstem and spinal cord anterior horn. Dysfunction of lower motor neurons causes muscle atrophy, fasciculations, and weakness, while dysfunction of upper motor neurons results in spasticity, weakness, hyperreflexia, and pathological reflexes. Cognitive and behavioral impairment are also common and can be seen in up to 50% of patients with ALS [2].

The estimated prevalence of ALS is 5 in 100,000 people in the United States [3] and 2.6–3.0 in 100,000 people in European populations [2]. It is more common in men than in women with a ratio 1.6 to 1. The majority of the cases are sporadic. The mean age at symptom onset is 56 years in sporadic ALS and 46 years in familial ALS [4]. ALS is debilitating and lethal. The disease is characterized by progressive facial, bulbar, tongue, limb, and respiratory muscle weakness with premature death caused by respiratory failure. The median survival is 2–3 years from symptoms onset. The older age at onset, bulbar onset, cognitive impairment, and certain genotypes are associated with a more rapid disease progression and a shorter lifespan [2, 4, 5].

About 10% of patients with ALS have a family history of the disease. Over two-thirds of FALS and 10% of sporadic ALS can have genetic causes identified [4]. More than 30 genes have been linked to FALS [6, 7]. The most common genetic cause of ALS is a hexanucleotide G4C2 repeat expansion (>30 repeats) in the chromosome 9 open reading frame 72 gene (C9orf72), which accounts for 30–40% of FALS, and it also causes frontotemporal dementia [8, 9]. SOD1 is the first gene that is linked to FALS [10, 11]. SOD1 gene mutations account for about 20% of FALS and up to 7% of sporadic ALS [12–15]. Transactive response DNA binding protein 43 KDa (TDP-43) accumulation is a feature of ALS. It is linked to frontotemporal dementia. Mutations in TARDBP, the gene that encodes TDP-43, account for about 5% of FALS. Mutations in the fused in sarcoma gene (FUS) also account for about 5% of FALS [4, 6].

The diagnosis of ALS is made based on the clinical features, EMG findings, and absent causative lesions in the brain, spinal cord, or nerve roots. The revised El Escorial criteria are considered the gold standard for the diagnosis of ALS [16]. Genetic testing can help confirm many cases of FALS. A muscle biopsy is not needed. However, as seen in our case, the diagnosis of FALS with SOD1 gene mutations can be missed or significantly delayed due to the lack of sufficient ALS clinical features at the initial presentation, co-existing spine spondylosis, confusing CK elevation, and ignorance of a positive family history.

Our patient was initially misdiagnosed with L/S polyradiculopathy because his initial symptoms were asymmetrical lower extremity weakness of pure lower motor neuron nature. His initial EMG showed right > left, L5 and S1 radiculopathies, and L/S spine MRI did show disc herniation and spinal stenosis at L4-5 and L5-S1. Radiculopathy from spine degenerative changes is not uncommon at age 50s. However, the scope of his leg weakness cannot not be fully explained by the structural abnormalities of his spine. Worsening of the leg weakness despite a successful laminectomy strongly argues against the L/S radiculopathy being the only or major cause of his leg weakness. It is well known that FALS with SOD1 gene mutations can present predominantly with lower motor neuron weakness affecting one segment at the early stage [12–14], which can mimic polyradiculopathy. Therefore, making a correct diagnosis at the early stage of the disease can be quite challenging. Frequent neurological follow-up evaluation, careful correlation of clinical presentation with EMG and MRI findings, and obtaining a detailed family history are needed to raise a high clinical suspicion for a FALS. Our patient did not tell his outside neurologist about the family history of ALS. He did not think he had ALS as his disease course was very different from his father’s. His father’s disease had a rapid progression, and he died of ALS less than 2 years after the symptom onset. Intra-familial phenotypic heterogeneity is common in FALS causes by an SOD1 mutation. The length of survival is variable.

Our patient was also misdiagnosed with a myopathy because of the CK elevation above 1,000 U/L. The moderate CK elevation led to muscle biopsies, and the chronic myopathic changes on the biopsies misled further. In our patient at age 50s with asymmetrical leg weakness and moderate CK elevation without upper motor neuron signs at the time of evaluation, a myopathy such as inclusion body myositis would be a reasonable consideration. However, it is worth noting that mild and moderate CK elevation can be seen not only in myopathies but also in a variety of motor neuron diseases, including sporadic ALS [17], Kennedy’s disease [18, 19], spinal muscular atrophy [20], and post-polio syndrome [21]. The etiology of CK elevation in motor neuron diseases is unclear. It is thought to be related to active denervation, but one study showed that the degree of CK elevation did not correlate with the degree of denervation noted in the EMG study [22]. It is not uncommon for a muscle biopsy to show both neurogenic changes and chronic myopathic changes in a motor neuron disease as seen in our case. The chronic myopathic changes have been reported in several motor neuron diseases, including ALS, spinobulbar muscular atrophy, and post-polio syndrome [19, 23–25]. They are attributed to the longstanding denervation, as chronic denervation can cause pseudomyopathic changes [26]. The neurogenic changes are usually prominent in motor neuron diseases such as ALS and spinobulbar muscular atrophy. These changes may include esterase-positive denervated atrophic fibers, pyknotic nuclear clumps, target or targetoid fibers, grouped atrophy, and rare fiber type grouping. Chronic myopathic changes in ALS and spinobulbar muscular atrophy may include increased fiber size variation with the presence of both atrophic and hypertrophic fibers, increased number of internalized nuclei, split fibers, and endomysial fibrosis [19, 25]. Occasional necrotic fibers, regenerating fibers, and minimal inflammation may also be present [19]. It has been shown that type grouping of normal-sized fibers is common in peripheral neuropathy but rare in motor neuron diseases, and that grouped atrophy in motor neuron diseases or motor neuropathies usually consists of mixed type 1 and type 2 atrophic fibers [27].

Patients with ALS are best managed by ALS clinics which can provide multidisciplinary care. The disease is debilitating and lethal. The treatment goal is to improve quality of life and prolong survival. There are currently two disease-modifying drugs approved by the US Food and Drug Administration (FDA) for ALS, including riluzole and Edaravone. Riluzole, which blocks the release of glutamate, was approved for ALS in 1995. It showed to provide a survival benefit of approximately 3 months [28, 29]. Edaravone, a free radical scavenger, was approved for ALS in 2017. It showed benefit in treating a small subset of patients at an early stage of ALS [30]. The symptomatic management includes rehabilitation, noninvasive ventilation support, swallow evaluation with diet modification or gastrostomy placement, nutritional support, cognitive and behavioral evaluations, and control of pseudobulbar affect, sialorrhea, limb spasticity, depression, fatigue, pain, and muscle cramps.

Pearls