Table 3.

Disorders to Consider in the Differential Diagnosis of ECHS1 Deficiency (ECHS1D)

DiffDx DisorderGene(s)MOIClinical Features of DiffDx Disorder
Overlapping w/ECHS1DDistinguishing from ECHS1D
Primary pyruvate dehydrogenase complex deficiency (PDCD) DLAT
DLD
PDHA1
PDHB
PDHX
PDK3
PDP1 		AR
XL
  • Pyruvate dehydrogenase complex deficiency
  • Lactic acidosis
  • ↑ pyruvate
  • Nl lactate to pyruvate ratio
  • Long philtrum
  • Corpus callosum hypoplasia
  • May be a complete phenocopy 1
  • Persons w/ECHS1D may have abnl acylcarnitine profile or urine organic acids not typically seen in primary PDCD.
3-hydroxyisobutyryl-CoA hydrolase deficiency (HIBCHD)
(OMIM 250620)		 HIBCH AR
  • Lactic acidosis
  • Basal gangliar lesions
  • ↑ 2-methyl-2,3-dihydroxybutyrate
Organic acid abnormalities typically more pronounced in HIBCH
FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome FBXL4 AR
  • Neonatal/primary lactic acidosis
  • Variable cardiomyopathy
  • FBXL4 deficiency typically has more striking hyperammonemia.
  • ATP synthase deficiency typically has more prominent 3-methylglutaconic aciduria.
  • ECHS1D may be suspected (rather than FBXL4 or TMEM70 deficiency) if 2-methyl-2,3-dihydroxybutyrate is present or lactate-to-pyruvate ratio is nl.
Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 (OMIM 614052) TMEM70
Mitochondrial complex I deficiency due to ACAD9 deficiency
(OMIM 611126)		 ACAD9
Other Leigh syndromes
(See Nuclear Gene-Encoded Leigh Syndrome Overview & Mitochondrial DNA-Associated Leigh Syndrome and NARP.)		>60 genesAR
mt
XL
  • T2 hyperintensity of the basal ganglia
  • Dystonia
  • Developmental regression
  • Lactic acidosis
ECHS1D may be clinically indistinguishable from other Leigh syndromes.
Paroxysmal exercise-induced dyskinesia & epilepsy
(See Glucose Transporter Type 1 Deficiency Syndrome.)		 SLC2A1 AD
AR 2		Paroxysmal exercise-induced dystoniaNl brain MRI
Paroxysmal kinesogenic dyskinesia
(See PRRT2-Associated Paroxysmal Movement Disorders.)		 PRRT2 AD
AR 2		Paroxysmal dystonia (may be exercise induced)Nl brain MRI
Familial paroxysmal nonkinesigenic dyskinesia PNKD AD
Pyruvate carboxylase deficiency PC AR↑ lactate, pyruvate, & ammonia
  • More striking hyperammonemia
  • Ketonuria
  • Nl organic acids

AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; mt = mitochondrial; nl = normal; XL = X-linked

1.
2.

Autosomal recessive inheritance is rare.

From: Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency

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