Table 2.

Movement Disorders to Consider in the Differential Diagnosis of NKX6-2-Related Disorder

DisorderGene(s)MOIOverlapping Clinical FeaturesDistinguishing Clinical Features
OnsetMovement disorderBrain MRIOther
Pelizaeus-Merzbacher disease (PMD) (See PLP1 Disorders.) PLP1 XLInfancy or early childhoodPyramidal, extrapyramidal, & cerebellarDiffuse hypomyelination; cerebellar atrophyEarly-onset nystagmusNull PLP1 variants are assoc w/mild demyelinating neuropathy & reduced levels of N-acetyl aspartate in cerebral white matter.
Pelizaeus-Merzbacher-like disease 1 (PMLD1) GJC2 AREarly childhoodPyramidal, extrapyramidal, & cerebellarDiffuse hypomyelination
  • Very similar to NKX6-2-related disorder
  • DD & speech delay
  • Preservation of cognition
In PMLD1:
  • Thinning of the corpus callosum in some
  • No cerebellar atrophy on MRI
POLR3-related leukodystrophy POLR3A
POLR3B
POLR1C 		AREarly childhoodPyramidal, extrapyramidal, & cerebellarDiffuse hypomyelinationIn POLR3-related leukodystrophy:
  • Abnormal dentition
  • Hypogonadotropic hypogonadism
Hypomyelination w/atrophy of basal ganglia & cerebellum (H-ABC) (See TUBB4A-Related Leukodystrophy.) TUBB4A ADInfancy or childhoodPyramidal & cerebellarDiffuse cerebral hypomyelinationMotor DDIn H-ABC:
  • Abnormalities of basal ganglia, esp atrophy (a classic sign)
  • Aphonia or "whispering" dysphonia may be a feature. 1
Salla disease (See Free Sialic Acid Storage Disorders.) SLC17A5 ARBirthPyramidal & extrapyramidalHypomyelination
  • Psychomotor retardation
  • Seizures
In severe form of Salla disease:
  • Severe DD
  • Coarse facial features
  • Hepatosplenomegaly
  • Cardiomegaly
  • Death usually in early childhood

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; XL = X-linked

1.

TUBB4A pathogenic variant c.4C>G causes the adult-onset disorder laryngeal dysphonia or whispering dysphonia (also known as DYT4 dystonia), with normal MRI.

From: NKX6-2-Related Disorder

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