Case presentation

An older man aged 47 years, serving as a soldier and having a background history of type 2 diabetes mellitus and dyslipidemia, presented with a complaint of poor, slurred speech that is progressing over four years. His diabetes and dyslipidemia were well controlled using oral hypoglycemic and lipid-lowering agents. No history of a previous cerebral event or traumatic brain injury, as well as no exposure to neurotoxic substances, was identified.

History of present illness

The first symptom was a mild change in the quality of speech. Family members noticed a change in the patient's articulation and the consonant pronunciation became more problematic. The speech was reported to be monotonous, slow, and increasingly difficult to comprehend.

Although the speech disturbance was progressive, no dysphagia, aspiration, or nasal regurgitation was noted, A mild cough in the process of swallowing thin liquids was reported three years later, but in general, swallowing was still intact. No visual symptoms, including diplopia and blurred vision, occurred. The patient did not complain of weight loss, limb weakness, muscle wasting, fasciculation, sensory symptoms, or incontinence of bladder and bowel. There were no reported variations in predominantly diurnal symptoms, which is why neuromuscular junction disorders were less probable.

The gait was maintained till the early stage, but slight instability was also observed later, especially when walking on uneven surfaces. Independent ambulation and work-related activities were acceptable. There was no history of cognitive impairment.

Family history

The family history revealed that there was a younger brother, age 42 years old, who presented with similar symptoms, but with earlier onset of ataxia and dysarthria at the age of 36. The consequence of these problems includes the development of dysphagia with progressive gait ataxia, resulting in his dependence on a wheelchair by the age of 40. The parents did not show any similar symptoms that would move towards an autosomal recessive inheritance pattern. Family history did not show any known consanguinity-related members of the family, as there had been no other family members diagnosed with hereditary ataxias or neurodegenerative disorders.

Figure 1: Pedigree diagram of family history. Two affected brothers with dysarthria and gait imbalance.

Neurological examination

Upon examination, the patient was alert and oriented to time, place, and person with normal higher mental abilities. There was a notable speech deficiency, slow, monotonic production with low articulation, which is indicative of cerebellar dysarthria. Neurological examination of cranial nerves demonstrated normal movements of the eyes with no nystagmus or ptosis. The tongue was midline, without fasciculations or atrophic appearance, with the palate raised equally. There was no bulbar palsy.

Motor exam showed the presence of normal bulk and tone of all four extremities, with full strength being observed 5/5 on the Medical Research Council (MRC) scale. None of the involuntary movements, tremors, or dystonic postures. Reflexes in lower and upper limbs were brisk (grade 3+) without progressive occurrence of clonus. His plantar responses were bilateral flexor. Also, there was preservation of sensory features of touch, pain, vibration, and proprioception.

The cerebellar examination indicated that the patient has poor performance on tandem gait and heel-to-shin tests, on the left side. Finger-to-nose test was normal. Romberg's test was negative. The patient could walk without walking aids.

Systemic examination

No significant changes were noted in abdominal, respiratory, and cardiovascular examination. No skin, skeletal, or scoliosis or winging of the scapula was found. The muscles were not atrophied and had no fasciculations. The risk of an inherited disorder increased due to a strong family history (particularly a sibling who was affected and showed more severe symptoms). The reliance on the lack of motor neuron manifestation, the presence of sensory impairment, diurnal variations, or metabolic anomalies all pointed to the rejection of more prevalent acquired factors.

Treatment and follow-up

The patient was managed conservatively with supportive care. Speech therapy was initiated to improve communication, but he stopped after a few sessions as he didn't feel much improvement. He was also referred to physiotherapy to improve his gait, but he did not follow up with the physiotherapist. According to the patient, he is satisfied with his gait and motor power. His diabetes and dyslipidemia were controlled with oral medications: metformin 500 mg twice daily and atorvastatin 20 mg once daily. On follow-up, the patient showed slow progression of dysarthria with mild gait instability but remained independently ambulatory with no dysphagia. No new neurological deficits were observed.

Investigations

To exclude acquired, metabolic, and structural causes, a thorough panel of investigations was carried out to assess progressive dysarthria and moderate cerebellar signs before considering genetic testing.

Neuroimaging

Brain magnetic resonance imaging (MRI), including T1-weighted axial and T2-weighted sagittal sequences, revealed no signal abnormalities (Figures 2, 3). No instances of cerebellar hemisphere, vermis, or cerebral white matter signal abnormalities were observed. No subcortical or cortical ischemic change, demyelination, or space-occupying lesions and no cerebellar or brainstem atrophy was noted. Usually, cerebellar atrophy is observed in hereditary ataxias, which exhibit a volume-depleting effect on the progression of the disorder. This common imaging finding further complicated the diagnostic process, as it could be misinterpreted to suggest a non-degenerative etiology of the disease at its early onset [15]. Although this patient had his symptoms for four years, no clear atrophic changes of the cerebellum were observed.

Figure 2: T1 brain MRI (magna (axial section)). Blue arrows identify the bilateral cerebellar hemispheresThe brain MRI shows normal brain structure of bilateral cerebellar hemispheres with no lesions or atrophy identified.

Figure 3: Brain T2 sagittal section, with arrow identifying the cerebellum with normal signal intensity.

Nerve conduction study

Nerve conduction studies (NCS) of lower-limb parameters were within normal limits, with no evidence of demyelination or axonal loss. The detailed NCS findings are summarized in Tables 1, 2.

Nerve | Side | Distal Latency (ms) | CMAP Amplitude (mV) | Conduction Velocity (m/s) | F-Wave Latency (ms)
Tibial nerve (motor) | Right | 4.1 | 10.2 | 48 | 48.3
Tibial nerve (motor) | Left | 4.2 | 9.8 | 47 | 49.1
Common fibular nerve (motor) | Right | 3.9 | 4.8 | 46 | 47.6
Common fibular nerve (motor) | Left | 4.0 | 4.6 | 47 | 48.2

Nerve | Site | Latency (peak) (ms) | Norm | Amplitude (p‑p) (µV) | Norm | Segment | Distance (cm) | CV (peak) (m/s) | Norm
Left Sural Sensory | Calf - lateral malleolus | 2.4 | < 4.0 | 20 | > 5.0 | Calf - lateral mall | 14 | 58 | > 35
Right Sural Sensory | Calf - lateral malleolus | 2 | < 4.0 | 28 | > 5.0 | Calf - lateral mall | 14 | 70 | > 35

Figures 4-7 depict the results of the nerve conduction study of bilateral (left and right) motor tibial and fibular nerves. The study showed normal compound muscle action potential (CMAP) waves of both motor nerves at different stimulation sites with normal wave, latency, amplitude and conduction velocity (CV).

Figure 4: Left tibial motor nerve conduction study recording from abductor hallucis brevis (AHB) muscle: stimulation at ankle, popliteal fossa

Figure 5: Left fibular motor nerve NCS recording from (EDB) muscle. Stimulation sites: ankle, below fibular head, and above fibular neckNCS: Nerve conduction study; EDB: extensor digitorum brevis (EDB) muscle.

Figure 6: Right tibial motor nerve conduction study recording from abductor hallucis brevis (AHB) muscle: stimulation at ankle, and popliteal fossa

Figure 7: Right fibular motor nerve NCS recording from the EDB muscle. Stimulation sites: ankle, below fibular head, above fibular neckNCS: nerve conduction study; EDB: extensor digitorum brevis.

Figures 8-11 show the F-wave recordings of bilateral tibial and peroneal nerves. The response was normal and normal latency values were observed, which indicate that there was no axonal damage of the proximal or distal nerves.

Figure 8: Right tibial F-wave. Recording from AHB muscle, stimulation at ankleAHB: Abductor hallucis brevis.

Figure 9: Left tibial F-wave. Recording from AHB muscle, stimulation site: ankleAHB: Abductor hallucis brevis.

Figure 10: Left fibular F-waves recording from EDB muscle. Stimulation site: ankle.

Figure 11: Right fibular F-wave. Recording from EDB muscle; stimulation site: ankleEDB: Extensor digitorum brevis.

Figures 12, 13 represent the results of the right and left sural nerve conduction study, showing normal sensory nerve action potential wave (SNAP) with normal values of amplitude and conduction velocity.

Figure 12: Left sural nerve (sensory) NCS. Recording site: posterior ankle; stimulation site: Posterior lateral calf.NCS: Nerve conduction study.

Figure 13: Right sural nerve (sensory) NCS. Recording site: posterior ankle; stimulation site: posterior lateral calfNCS: Nerve conduction study. This study indicates normal sural sensory nerve conduction study.

Nerve conduction studies (NCS) of the lower limbs were performed to evaluate for neuropathy disorders. Motor and sensory nerve conduction parameters were within normal limits, with no evidence of demyelination or axonal loss. These findings ruled out the possibility of Friedrich ataxia, which may manifest as dysarthria, ataxia, and neuropathy [16].

Laboratory workup

Laboratory investigations are summarized in Table 3. All values were within normal limits and did not suggest a metabolic or systemic cause. Collectively, these findings were counterarguments to metabolic and systemic explanations of progressively dysarthric patients [17].

Parameter | Patient Value | Reference Range
Glucose | 5.8 mmol/L | 3.4-8.7 mmol/L
Hemoglobin | 152 g/L | 135-180 g/L
WBC | 4.9×10⁹/L | 4-11×10⁹/L
Vitamin B12 | 253 pmol/L | 138-652 pmol/L
TSH | 3.58 mIU/L | 0.35-4.94 mIU/L
Vitamin D | 73.3 nmol/L | 50-125 nmol/L
Alpha-fetoprotein | 3 ng/mL | <10 ng/mL
Copper | 13.43 µmol/L | 12-18 µmol/L
Ceruloplasmin | 0.28 g/L | 0.20-0.60 g/L
RBC | 5.1×10¹²/L | 4.5-6.1 ×10¹²/L
Hematocrit (Hct) | 0.453 L/L | 0.42-0.54 L/L
MCV | 89.1 fL | 76-96 fL
MCH | 29.9 pg | 27-32 pg
MCHC | 335 g/L | 320-350 g/L
RDW | 13.1% | 11.5-14.5%
Total Cholesterol | 4.45 mmol/L | <5.18 mmol/L
HDL Cholesterol | 1.12 mmol/L | >1.55 mmol/L
LDL Cholesterol | 2.98 mmol/L | <2.6 mmol/L
Triglycerides | 1.81 mmol/L | <1.7 mmol/L
Uric Acid | 375 μmol/L | 210-420 μmol/L
Phosphorus | 1.1 mmol/L | 0.74-1.52 mmol/L
Adjusted Calcium | 2.2 mmol/L | 2.1-2.55 mmol/L
Vitamin E (α-tocopherol) | 14.9 μmol/L | 11.6-46.4 μmol/L
Ethanol | <2.1 mmol/L | <2.2 mmol/L
Toxicology screen (cannabinoids, cocaine, amphetamines, barbiturates, opiates, benzodiazepines) | Negative (all) | Negative

Genetic analysis

Since structural lesions were not detected on MRI, metabolic workup showed normal parameters. Given the strong family history of ataxia, genetic assessment was undertaken. Whole-exome sequencing (WES) was done. A homozygous identity nonsense mutation in the GDAP2 gene was recognized with bioinformatic analysis (c.475C>T, p.). Gln159*). This type of mutation introduces a premature stop codon in exon 5 of 14, which is expected to cause loss of functional protein and results in the production of a shortened protein that is likely non-functional.

Variant interpretation was performed according to the American College of Medical Genetics and Genomics (ACMG) guidelines [18]. The mutation's truncating nature is not present in population databases. The mutation had not appeared in the literature before, which means that it is a new addition to the mutational phenotype of SCAR27. The evidence that this mutation carries validity comes from the patient's brother, who has ataxia and slurred speech, was tested and showed a similar genetic mutation of GDAP2 gene c475C>T p.(GIn159*), which indicates that this variant is pathologic.

Differential exclusion

The results of imaging, laboratory, and electrophysiological studies together served to rule out a number of possible differential diagnoses. There were no signs of upper/lower motor neuron lesions on examination, which suggests amyotrophic lateral sclerosis. Multiple sclerosis, cerebrovascular disease, and structural cerebellar degeneration were eliminated by normal neuroimaging. The absence of metabolic abnormalities also ruled out vitamin E deficiency, Wilson disease, and any other treatable ataxia. The availability of an established pathogenic form of GDAP2 offered an established molecular diagnosis of an autosomal recessive spinocerebellar ataxia type 27 (SCAR27). The studies revealed that although MRI was normal and no specific laboratory results were detected, genetic tests played a pivotal role in establishing the diagnosis. Given these conditions, further genetic investigation in patients with unexplained progressive neurological symptoms is especially noteworthy when a positive family history is present.