Diagnosing amyotrophic lateral sclerosis (ALS) is a complex and challenging task, requiring careful consideration of various factors. Differential diagnosis for conditions that mimic ALS is critical to ensure accurate and timely treatment. Among these conditions, distal hereditary motor neuropathy type 5 (dHMN-V) stands out as a significant differential diagnosis due to its clinical resemblance to ALS. dHMN-V is associated with a specific gene variant in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene [1]. It presents with distinct clinical features: progressive distal muscle weakness, pure motor involvement primarily in the upper limbs, and absence of sensory disturbances. These resemblance of clinical phenotypes makes it important to differentiate dHMN-V from ALS. In this case report, we present a 21-year-old female patient whose clinical journey underscores the significance of distinguishing dHMN-V as a potential alternative diagnosis in cases initially resembling ALS.
CASE
A 21-year-old female visited our neurology department with 6 years history of progressive muscle weakness in the distal muscles of the upper limbs (III-1 in Fig. A). Four years later from the initial onset date, the patient reported difficulty walking, frequent tripping, and weakness in foot dorsiflexion and plantarflexion. She also complained of tremor-like involuntary movements in both hands. She denied any sensory disturbances, sphincter dysfunction. There was no significant family history of neurological disorders.
Upon examination, the patient showed muscle wasting and weakness, predominantly in upper extremity especially intrinsic hand muscles. Marked weakness in finger flexion and extension of Medical Research Council (MRC) grade 3 was recorded, with mild weakness (MRC grade 4+) in right hip flexion. Pes cavus was also present while the knee extensors and flexors, as well as other upper limbs, appeared unaffected. Deep tendon reflexes were normoactive to hyperactive on upper and lower extremities. Sensory examination was unremarkable. Upon close examination, irregular and repetitive jerky movements resembling dystonic tremor were seen in the fingers and the toes. There were also minipolymyoclonus of small amplitudes in bilateral wrists and ankles. The clinical presentation of progressive distal muscle weakness and atrophy as a lower motor neuron sign coincided with hyperreflexia as an upper motor neuron sign raised suspicion of a motor neuron disease, especially ALS.
The initial workup included electrophysiology studies, nerve conduction studies (NCS) and electromyography (EMG). NCS revealed low amplitude of compound muscle action potential recorded over right abductor pollicis brevis (APB) with median nerve stimulation (Table). EMG showed active denervation potentials in bilateral 1st dorsal interossei and right APB, confirming a lower motor neuron involvement. Repeated nerve stimulation test was unremarkable. Routine complete blood test, blood chemistry was normal. Brain and cervical spine magnetic resonance imaging was normal.
Since she was young age onset patient, whole exome sequencing was analyzed for any genetic variants. Interestingly, a heterozygous pathogenic variant (NM_032667.6; c.263A>G, p.Asn88Ser) in BSCL2 gene was identified. Subsequently genetic test for her parents were done and both her parents (II-6, II-7 in Fig. A) did not have the gene variant, identifying this variant is de novo (Fig. B). Based on the clinical presentation, electromyographic findings, and genetic test results, the patient was diagnosed with dHMN-V. She was discharged with a plan for close observation, along with the administration of a vitamin supplement serving as an antioxidant.
DISCUSSION
ALS affects motor neurons leading to the progressive deterioration of both upper motor neurons and lower motor neurons. Diagnosis of ALS relies on the clinical symptoms. Differential diagnosis is crucial because potential curative treatments exist for certain ALS mimic diseases [2]. ALS mimics include wide variety of diseases. dHMN-V caused by BSCL2 variant is also one of ALS mimics that show progressive degeneration of motor neurons in distal upper limbs, especially hand muscles [3]. dHMN-V is mostly limited to distal upper extremity and very slowly progressed in nature. However, early stage at diagnosing ALS patients with upper extremity weakness is confusing because symptoms could only appear in upper limbs [2,3].
BSCL2 gene encodes seipin, a protein that plays a vital role in lipid droplets formation and regulation of excitatory synaptic transmission. Variant of seipin is believed to provoke endoplasmic reticulum stress, inducing cell toxicity [4]. Known pathogenic variants are p.N88S and p.S90L and p.S90W variants [5-8]. Patients with the same genetic variant may exhibit different clinical phenotypes and show varying degrees of penetrance [5,9,10]. The variant of this patient, p.N88S variant, also show variable phenotypes. Previous study, Auer-Grumbach et al. [5] subdivided clinical phenotypes into six groups: subtypes 1 (no symptoms), subtypes 2 (subclinical phenotype), subtypes 3 (dHMN-V phenotype), subtypes 4 (Silver syndrome phenotype), subtypes 5 (Charcot-Marie-Tooth phenotype), and subtypes 6 (hereditary spastic paraplegia phenotype).
In this case, the combination of progressive muscle weakness and atrophy in the peripheral areas, suggesting lower motor neuron participation, along with heightened reflexes, which point to upper motor neuron impairment, has raised concerns about the possibility of ALS. Moreover, the disease’s progression towards the lower extremities, rather than being confined to the upper extremities, along with its relatively rapid course, poses additional challenges to prompt diagnosis. However, genetic screening confirmed de novo variant of BSCL2 gene and diagnosis of dHMN-V. The patient exhibited some features of typical dHMN-V, which are slowly progressive weakness predominant in the upper limbs and pes cavus with mild involvement of the lower extremities. In addition to such features, dystonic tremor and minipolymyoclonus in the distal limbs were observed unlike previously reported cases.
This case report firstly highlights the importance of considering dHMN-V as a differential diagnosis in patients presenting with clinical features resembling ALS. Secondly, it expands the clinical spectrum associated with BSCL2 variant. Minipolymyoclonus, described as an atypical clinical feature in this case, may be one of clinical manifestations associated with dHMN-V. It is essential for healthcare practitioners to consider this phenomenon when conducting examinations on patients. Genetic test plays a crucial role in confirming the diagnosis and guiding appropriate management strategies, including genetic counseling and potential therapies targeting the underlying molecular defect. Early and accurate diagnosis is essential for appropriate patient care, counseling, and support for affected families.
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