Table 4.

Disorders to Consider in the Differential Diagnosis of ISCA1-MMDS

DisorderGeneMOIClinical Features of Differential Diagnosis Disorder
Overlapping w/ISCA1-MMDSDistinguishing from ISCA1-MMDS
Multiple mitochondrial dysfunctions syndrome 1 (OMIM 605711) NFU1 AR
  • Feeding difficulties, muscle weakness, decreasing responsiveness, neurologic regression
  • WM lesions on brain MRI
  • Pulmonary hypertension, obstructive vasculopathy
  • Spongiform degeneration, WM necrosis
Multiple mitochondrial dysfunctions syndrome 2 (OMIM 614299) BOLA3 AR
  • Visual impairment, spasticity
  • Leukodystrophy
  • Onset in infancy
  • Cardiomyopathy, hepatomegaly
  • Extrapyramidal signs, ataxia, myoclonus
Multiple mitochondrial dysfunctions syndrome 3 (OMIM 615330) IBA57 ARWM abnormalities
  • Onset in utero, IUGR
  • Microcephaly, dysmorphic features (retrognathia, high-arched palate, widely spaced nipples), arthrogryposis, severe hypotonia
  • Hypoplasia of corpus callosum & medulla oblongata
ISCA2-related mitochondrial disorder (multiple mitochondrial dysfunctions syndrome 4) ISCA2 AR
  • Loss of developmental milestones, spasticity, nystagmus
  • WM abnormalities
  • Lactic acidosis
↑ plasma & CSF glycine levels
Metachromatic leukodystrophy (See Arylsulfatase A Deficiency & OMIM 249900.) ARSA
PSAP 		AR
  • Neurologic regression
  • Leukodystrophy
  • Spasticity
↑ urinary sulfatide excretion
Krabbe disease GALC AR
  • Neurologic regression, spasticity
  • Leukodystrophy
↓ galactocerebrosidase activity (See Krabbe disease.)
Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation DARS2 ARNeurologic regression
  • Spotty or confluent cerebral WM changes w/relative sparing of subcortical WM
  • Involvement of dorsal columns, lateral corticospinal tracts, & medial lemniscus in medulla oblongata
Childhood ataxia with central nervous system hypomyelination/vanishing white matter EIF2B1
EIF2B2
EIF2B3
EIF2B4
EIF2B5 		AR
  • Neurologic regression, spasticity
  • Leukodystrophy
  • Unsteady gait
  • MRI findings:
    bilateral symmetric diffuse changes in cerebral hemispheres isointense w/CSF;
    cystic breakdown of WM on proton density or FLAIR images;
    mild-to-severe cerebellar atrophy
  • Ovarian dysgenesis in females
Canavan disease ASPA AR
  • Neurologic regression
  • Leukodystrophy
  • Macrocephaly
  • MRI findings:
    symmetric & diffuse WM changes in cerebral cortex & subcortical region;
    less marked involvement of cerebellum & brain stem
  • ↑ N-acetyl-L-aspartate in urine
Alexander disease GFAP AD
  • Neurologic regression, spasticity
  • Leukodystrophy
  • Macrocephaly
  • MRI findings:
    cerebral WM abnormalities w/frontal predominance;
    basal ganglia & thalami may incl atrophy &/or altered signal intensity;
    medulla & midbrain involvement
Leigh syndrome (See Mitochondrial DNA-Associated Leigh Syndrome and NARP & Nuclear Gene-Encoded Leigh Syndrome Overview.)>75 genesAR
XL
mt
  • Neurologic regression
  • ↑ lactate in MR spectroscopy
  • Hypertrophic cardiomyopathy
  • Hypertrichosis
  • Renal tubulopathy
  • Liver involvement
  • MRI findings:
    basal ganglia involvement;
    bilateral symmetric T2-weighted hyperintensities in basal ganglia &/or brain stem

AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; IUGR = intrauterine growth restriction; MOI = mode of inheritance; mt = mitochondrial; WM = white matter; XL = X-linked

From: ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome

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