Clinical Reasoning: A 23-Year-Old Woman Presenting With Cognitive Impairment and Gait Disturbance

Section 1

A 23-year-old woman presented with a 3-year progressive history of forgetfulness, unsteady gait, and falls. She had no medical history.

She was the product of a normal delivery, with normal developmental milestones. Until her late teens, she played field sports capably and was an accomplished dancer. Academically, she was consistently in the middle range of her classes and completed a higher diploma in business management.

After college, she struggled in an administrative office job, which surprised her parents, and was made redundant. Thereafter, she undertook a retail job in a clothing store. She also had difficulties there in operating cashier tills and IT systems. She was gifted a car for her 21st birthday but could not learn the appropriate sequencing to drive safely and abandoned the effort after several months. Her mother described that the patient often lost items irretrievably and frequently repeated herself. She needed constant reminders to bring personal items with her.

Her sporting and dancing prowess declined, and she incurred numerous falls, which she attributed to clumsiness. Sleep quality was good, but she felt fatigued by day. She denied low mood but became less talkative and withdrawn.

She was the oldest of a kinship of 3, with a brother aged 20 years and a sister aged 12 years; both were reported to be well. There was no other family history of neurologic disease or premature death. She did not drink, smoke, or use recreational drugs.

Neurologic examination revealed normal cranial nerves, normal tone, power, reflexes, and sensation. Her gait was predominantly characterized by dystonic posturing of her right leg and foot with more subtle posturing of her right upper limb while walking. She could not tandem gait. The Romberg test was negative. She scored 70/100 on Addenbrooke's Cognitive Examination Version 3 with salient frontal and executive dysfunction. Brain MRI revealed widespread periventricular and deep white matter signal changes with involvement of the corticospinal tracts and brainstem. There was associated white matter atrophy with ventriculomegaly, significant atrophy in the corpus callosum, and cerebellar atrophy (Figure).

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Figure Axial FLAIR and Sagittal T2 MRI Sequences Showing Frontal-Predominant Atrophy and Extensive White Matter Hyperintensity

There is also appreciable hyperintensity and atrophy involving the corpus callosum.

Section 2

The differential diagnosis for cognitive impairment and gait disturbance with white matter changes is broad. Several etiologic categories including inflammatory/autoimmune (less likely given the tempo of progression in this case), infectious (less likely given the absence of other infectious symptoms and more chronic temporal course), neoplastic (less likely due to pace of progression), and neurogenetic disorders (heredodegenerative and metabolic disorders) must be considered. Initial laboratory workup included complete blood count, erythrocyte sedimentation rate, renal/liver/bone/thyroid indices, creatinine kinase, serum protein electrophoresis, lactate, vitamin B12, folate, serum copper and ceruloplasmin, HIV and syphilis serology, antinuclear antibody, ANCA, antiphospholipid antibodies, and an extensive paraneoplastic antibody panel, all of which were normal or negative. CSF analysis including cytology was normal; oligoclonal bands were negative. EEG did not show any epileptiform activity. As initial bloodwork and an entirely normal CSF militated against a neuroinflammatory, infectious, or paraneoplastic etiology, a genetically mediated disorder, including a mitochondrial cytopathy or metabolic process, was suspected.

Section 3

Given the apparent absence of a family history in our case, an autosomal recessive process was considered. The differential diagnosis of leukodystrophies is broad (Table), and after considering them, serum amino acid profile, very long chain fatty acids, vitamins A and E, arylsulfatase A, cholestanol, and urinary organic acids were ordered. Lysosomal enzyme testing showed low arylsulfatase and elevated urinary sulfatides. Nerve conduction studies demonstrated a mild to moderate length-dependent large fiber, sensory-predominant, demyelinating polyneuropathy. The metabolic disease genetic panel revealed a homozygous pathogenic mutation in the ARSA gene; c.1283C>T (Pro428Leu), confirming the diagnosis of metachromatic leukodystrophy (MLD). Re-evaluation of the brain MRI demonstrated an MLD score of 21. Her other siblings were tested with consent; her brother harbored the same mutation. He acknowledged mild attentional deficits in the preceding months but no other symptoms. He had mild frontoexecutive deficits on cognitive testing, and brain MRI and neurophysiology findings were similar to those of his sister.

Section 4

Metachromatic leukodystrophy (MLD) is an inherited lysosomal disorder, which is progressive and incurable.³ In the adult form, the disease may progress over 20–30 years, although typically individuals reach maximum disability within 6–14 years after symptom onset (although there is variability in outcomes).⁴ After consulting expert opinion in Ireland and the United Kingdom, hematopoietic stem cell transplantation (HSCT) was offered to the siblings. The extensive risk profile was discussed; detailed serial capacity assessments were completed before seeking informed consent. Both patients were deemed capable of making an informed decision. Transplantation was delivered in a unit with metabolic experience in Manchester, UK. The male sibling received HSCT first. Graft failure ensued with profound aplasia, and he underwent a second HSCT; unfortunately, he developed transfusion-refractory pancytopenia and died of intracranial hemorrhage. Our 23-year-old female patient subsequently received HSCT. Status epilepticus complicated the immediate posttransplant phase, but she stabilized quickly and is now 24 months after HSCT. Both cognitive and motor functions have stabilized.