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Mitochondrial Disease with Heterozygous NUBPL Mutation

  • Background:
    • Mitochondrial disorders are considered in the differential diagnosis of diffuse white matter diseases. Given the heterogeneous clinical manifestations, many of these remain without a specific diagnosis.
    • NUBPL is a protein involved in the assembly of mitochondrial respiratory chain (MRC) complex I.
  • Clinical Presentation:
    • Patients with NUBPL mutation have been described presenting in the first 2 years of life with delayed motor development, spasticity, ataxia, and seizures. Cognition may vary from normal to profoundly impaired.
    • A more indolent presentation in this patient, with impaired cognition followed by a strokelike episode and seizures, may be related to the heterozygous MRC mutation.
  • Key Diagnostic Features:
    • Most patients with NUBPL mutations reveal elevated lactate in serum and CSF, and MRC complex I deficiency may be evident in muscle biopsy or fibroblast assay.
    • A characteristic MRI pattern has been described—initial T2-hyperintense lesions in the cerebellar cortex, deep cerebral white matter, and corpus callosum, sparing the U-fibers; signal changes in the supratentorial compartment gradually improve/resolve, while the cerebellar findings are progressive and additional brainstem abnormalities may appear.
    • This patient’s imaging pattern proved to be atypical given the absence of signal changes in infratentorial structures and the progression of supratentorial white matter hyperintensity (with late involvement of U-fibers). Furthermore, to date no medullary abnormalities have been described related to this MRC mutation. CSF was positive for 7 oligoclonal bands without serum correspondence. Muscle biopsy presented increased oxidative disease and signs of neurogenic atrophy. Genetic panel for leukodystrophies proved to be diagnostic.
  • Differential Diagnoses:
    • Multiple sclerosis represents a reasonable initial diagnostic hypothesis when managing an adult female patient with a diffuse white matter disease and spinal involvement on MRI, associated with positive oligoclonal bands on CSF.
    • The differential diagnosis should also include genetic small vessel diseases.
    • In CADASIL (heterozygous NOTCH3 mutations), the anterior temporal lobes and external capsules are classically affected; however, a more diffuse subcortical white matter disease pattern may be found, particularly in later stages or younger patients. In CARASIL (homozygous HTRA1 mutations), typical hyperintense lesions in the pons and cerebellar peduncles (“arc sign”) have been described in advanced stages; no infratentorial changes were encountered in our patient. Moreover, spinal cord involvement is uncommon in both entities.
    • A late-onset autosomal dominant disease caused by heterozygous HTRA1 variants has been related to diffuse white matter changes sparing the U-fibers with potential involvement of the corpus callosum, and thus should also be considered.
  • Treatment:
    • No current specific treatment for complex I deficiency disorders exists.
    • Treatment of seizures and spasticity should be privileged.
May 6, 2021

A 50-year-old woman with learning difficulties since childhood and behavioral changes since adolescence presented with acute left hemiparesis and ataxia at 41 years old. Progressive cognitive decline, motor impairment, and epileptic seizures ensued. Family history was irrelevant.

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