Table 3.

Inherited Disorders in the Differential Diagnosis of NKH

DisorderGene(s)MOIClinical FindingsLaboratory Findings
GCS cofactor deficiency 1 Lipoate deficiency 2 LIAS
LIPT2
BOLA3
GLRX5
IBA57
NFU1 		ARDD, seizures, spasticity, ataxia, optic atrophy, pulmonary hypertension, cardiomyopathy
  • ↑ plasma & CSF glycine levels
  • Deficient GCS activity
  • Deficient pyruvate dehydrogenase enzyme activity
Pyridoxine-dependent epilepsy 3 ALDH7A1 ARNeonatal epileptic encephalopathy responsive to pyridoxine treatment
  • ↑ plasma & CSF glycine levels
  • Deficient GCS activity
PNPO deficiency 3 PNPO ARSevere neonatal seizures & coma; ± apnea; seizures respond to pyridoxal 5'-phosphate treatment. 4
  • ↑ CSF glycine levels
  • Low CSF pyridoxal phosphate
PLPBP deficiency 3 PLPBP ARPresentation similar to PNPO deficiency
Abnormal regulation of GCS cblX (cobalamin X) 5 (See Disorders of Intracellular Cobalamin Metabolism.) HCFC1 XLMales: neonatal seizures
  • ↑ plasma & CSF glycine levels
  • Combined methylmalonic aciduria & hyperhomocysteinemia
Glycine transport defect GLYT1 encephalopathy SLC6A9 ARNeonatal encephalopathy, impaired consciousness, often poor respiratory drive, death usually < age 1 yr
  • ↑ CSF glycine (range: 21-33 μmol/L)
  • Normal plasma glycine & ↑ CSF:plasma glycine ratio
Inhibition of GCS activity Organic acidurias 6 (e.g., MMA, PA, IVA)Multiple genes (e.g., PCCA, PCCB, IVD, MMUT [MUT])Typically ARNeonatal encephalopathy, metabolic acidosis, hyperammonemia, ketones
  • ↑ plasma & CSF glycine levels but normal CSF:plasma glycine ratio
  • Abnormal urine organic acids (ketotic hyperglycinemia)

AR = autosomal recessive; CSF = cerebrospinal fluid; DD = developmental delay; GCS = glycine cleavage enzyme system; IVA = isovaleric acidemia; MMA = methylmalonic aciduria; MOI = mode of inheritance; NKH = nonketotic hyperglycinemia; PA = propionic acidemia; PLPBP = pyridoxal 5'-phosphate-binding protein; PNPO = pyridoxamine 5'-phosphate oxidase; XL = X-linked

1.

"Variant NKH" refers to glycine encephalopathy with elevated glycine levels and deficient GCS activity without GLDC or AMT pathogenic variants, most commonly due to deficiencies in the metabolism of GCS cofactors including lipoate deficiency and pyridoxal phosphate deficiency.

2.

Impaired lipoylation or deficient lipoate due to biallelic pathogenic variants in genes encoding either lipoate synthesis (e.g., LIAS and LIPT2) or in the synthesis of the iron-sulfur cluster necessary for the function of lipoate synthase (e.g., BOLA3, GLRX5, IBA57, or NFU1) [Baker et al 2014].

3.

Pyridoxal phosphate is a cofactor for the glycine cleavage enzyme system. Insufficient pyridoxal phosphate results in elevated glycine levels.

4.
5.
6.

"Ketotic hyperglycinemia" is a term used in the past to refer to genetic disorders in which GCS activity is secondarily inhibited in particular for several organic acidurias [Hayasaka & Tada 1983].

From: Nonketotic Hyperglycinemia

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