A 61-Year-Old Man With Weakness and Gait Dysfunction

A 61-year-old man presented with chronic progressive weakness and gait dysfunction. Four years prior, he developed progressive arm and leg weakness. He subsequently experienced recurrent falls, attributed to gait imbalance and tripping over his feet, and urinary incontinence. One year prior, his wife noted progressive memory loss (eg, getting lost when going to familiar places), dysarthria, and episodes of inappropriate laughter (ie, involuntarily laughing without a clear emotional trigger). He had a history of hypertension. There was no known history of a neurological disorder in his family. He had Ashkenazi Jewish ancestry in his maternal lineage. There was no known consanguinity. Neurological examination revealed impaired short-term recall (recalled 0 of 5 words at 5 minutes) and a pseudobulbar affect. His cranial nerve examination was notable for a spastic dysarthria without tongue atrophy/fasciculations. There was upper and lower extremity spasticity, atrophy of intrinsic hand and calf muscles, and mild weakness of his intrinsic hand and distal lower extremity muscles bilaterally. There was decreased large-fiber sensation distally in his lower extremities. Romberg sign was absent. Deep tendon reflexes were 3+ at the biceps and patellars and absent at the ankles. Plantar responses were extensor bilaterally. Cerebellar function was normal. The gait was spastic. Magnetic resonance imaging (MRI) of the brain showed confluent T2/fluid-attenuated inversion recovery (FLAIR) hyperintensity in the periventricular white matter involving the corticospinal tracts, posterior limb of internal capsule, external capsule, and medial lemniscus and corticospinal tracts at the pons and medulla (Figure). MRI of the cervical and thoracic spinal cord showed diffuse atrophy without signal abnormalities. Electromyography revealed a chronic sensorimotor axonal neuropathy and lumbosacral radiculopathies. He had normal levels of vitamin B₁₂, methylmalonic acid, copper, vitamin E, lactate/pyruvate, very long chain fatty acids, plasma/urine amino acids, and lysosomal enzymes, a normal bile acids profile, and negative infectious serologies (HIV, syphilis, and human T-lymphotropic virus). Cerebrospinal fluid analysis revealed normal cell counts, protein and glucose levels, oligoclonal band profile, and IgG index.

Figure.

Magnetic resonance imaging (MRI) of the brain showing fluid-attenuated inversion recovery hyperintensity involving the periventricular regions, corticospinal tracts, posterior limb of the internal capsule, the external capsule (A) the medial lemniscus and corticospinal tracts of the medulla, cerebellar peduncle, and the dentate nuclei (B, circle).

Discussion

The presentation was suggestive of adult polyglucosan body disease (APBD), and a multigene panel revealed a compound heterozygous pathogenic missense variant in the glycogen branching enzyme 1 (GBE1) gene (c.986A>C (p.Tyr329Ser) and c.691 + 2T>C (IVS5 + 2T>C)), confirming this diagnosis.¹ The Tyr329Ser variant is common in Ashkenazi Jewish patients.

APBD is a rare autosomal recessive neurodegenerative disorder, in the spectrum of glycogen storage disease type IV, caused by biallelic pathogenic GBE1 variants.^1–4 The clinical presentation is heterogeneous, but the core symptoms include progressive neurogenic bladder, gait dysfunction due to mixed upper and lower motor neuron involvement (ie, myeloneuropathy), and cognitive impairment at or after age 40 years.^1–4 Lower motor neuron involvement is due to a length-dependent axonal polyneuropathy and polyradiculopathies.^1–4 In severe cases, an Alzheimer disease–like dementia phenotype was previously reported.^1–4 The pace of progression is usually slow. In one of the largest series to date, the median age for onset of symptoms was 51 years and for wheelchair dependence and death was 63 and 70 years, respectively.⁴ Radiographic findings may be nonspecific and include widespread confluent and symmetric T2/FLAIR hyperintense white matter abnormalities in the periventricular regions, posterior limb of the internal capsule, and external capsule. Additional clues that (if present) suggest APBD include involvement of corticospinal tracts and medial lemniscus of the pons and medulla, superior cerebellar peduncles and dentate nuclei, and medullary and spinal cord atrophy.^1–4 Although nerve biopsy may show polyglucosan bodies, definitive diagnosisis established by genetic testing via targeted GBE1 sequencing, multigene panels that include GBE1, whole-exome sequencing or whole-genome sequencing.^2,3 Treatment is supportive and includes symptomatic management of spasticity, neurogenic bladder, dysautonomia, and cognitive decline.^2,3

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is caused by autosomal recessive variants in the DARS2 gene.⁵ Typical presentation occurs in early childhood, but adult-onset disease has been described.⁵ Core clinical features include slowly progressive cerebellar ataxia, lower-extremity predominant spasticity, and dorsal column dysfunction.⁵ Axonal neuropathy can occur. MRI reveals a distinct T2/FLAIR hyperintensity in the cerebral white matter sparing the U-fibers, involvement of posterior limbs of the internal capsule, splenium of the corpus callosum, trigeminal nerve tracts, cerebellum, and the dorsal column and lateral corticospinal tracts of the medulla and spinal cord.⁵ Features that allow distinction from APBD are an earlier age of onset, prominent cerebellar and sensory ataxia, and characteristic spinal cord signal abnormalities.⁵

LMNB-1–related autosomal dominant leukodystrophy (ADLD) presents between ages 40 to 60 years with dysautonomia followed by corticospinal tract and cerebellar dysfunction, resulting in spastic ataxia and tremors.⁶ MRI in ADLD can show T2/FLAIR hyperintensity predominantly in a frontoparietal distribution following the corticospinal tracts through the posterior limb of the internal capsule toward the medulla and upper and middle cerebellar peduncles.^6,7 Spinal cord atrophy is common and can be associated T2/FLAIR hyperintensity in the entire cord white matter.^6,7 Some distinguishing features from APBD are the different imaging pattern, sparing of the peripheral nervous system, and more prominent cerebellar dysfunction.⁶

Alexander disease is caused by autosomal dominant GFAP gene variants that can present across the lifespan, with adult onset occurring in approximately 33% of cases.⁸ The typical adult phenotype includes bulbar symptoms (eg, palatal myoclonus, dysarthria, dysphagia), cerebellar dysfunction, and corticospinal tract involvement resulting in spastic weakness.^8,9 Other features include sleep disorder, dysautonomia, and parkinsonism.⁸ A typical MRI finding is cervicomedullary atrophy with relative pontine sparing, known as the tadpole sign. ^8,9 Other potential findings include cerebellar signal abnormalities, contrast-enhancing lesions, and periventricular white matter T2/FLAIR hyperintensities.^8,9 Distinguishing features from APBD include sparing of the peripheral nervous system and lack of the extensive supratentorial signal abnormalities and extensive spinal cord atrophy seen in this case.^8,9

WHAT IS YOUR DIAGNOSIS?

1. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation.

2. LMNB11-related autosomal dominant leukodystrophy.

3. Adult polyglucosan body disease.

4. Adult-onset Alexander disease.

Diagnosis.

C. Adult polyglucosan body disease