Table 4. [Genes of Interest in the Differential Diagnosis of POLG-Related Disorders]. - GeneReviews®

Table 4.

Genes of Interest in the Differential Diagnosis of POLG-Related Disorders

Gene(s) ¹ / Genetic Mechanism	Disorder	MOI	Comment
ALDH7A1	Pyridoxine-dependent epilepsy – ALDH7A1 (pyridoxine-dependent epilepsy)	AR	Neonatal-onset progressive encephalopathy w/refractory seizures Targeted therapy: seizures are not well controlled w/ASMs but respond to large daily supplements of pyridoxine (vitamin B₆).
AMT GLDC	Nonketotic hyperglycinemia (NKH)	AR	Epilepsia partialis continua has been described in some affected persons. ²
ATP7A	Menkes disease (See ATP7A-Related Copper Transport Disorders.)	XL	Neonatal-onset progressive encephalopathy w/refractory seizures Usually present earlier in infancy than AHS
BCS1L	BCS1L-related disorders (incl GRACILE syndrome [OMIM 603358], Bjørnstad syndrome [OMIM 262000], & GRACILE syndrome-Bjørnstad syndrome overlap phenotype]	AR	The clinical scenario of a hepatoencephalopathy may appear similar to AHS at a single point in time, but mtDNA depletion is not part of the pathology described in those w/BCS1L pathogenic variants.
BTD	Biotinidase deficiency	AR	Neonatal-onset progressive encephalopathy w/refractory seizures Targeted therapy: Oral biotin. Compliance w/biotin therapy can prevent development of disease & also improves symptoms in symptomatic persons.
CACNA1A	CACNA1A-related early infantile epileptic encephalopathy (OMIM 617106)	AD	Severe infantile epileptic disorder that appears progressive at onset but usually plateaus into developmental arrest/delay
CACNB4	Idiopathic generalized epilepsy & myoclonic epilepsy (OMIM 607682) & episodic ataxia type 5 (OMIM 613855)	AD	Early-onset epileptic disorder that is often assoc w/myoclonic, generalized tonic-clonic, or absence seizures w/photosensitivity reported in some persons ³
CERS1 CSTB EPM2A GOSR2 KCNC1 KCTD7 LMNB2 NHLRC1 PRDM8 PRICKLE1 SCARB2 SEMA6B SLC7A6OS	Myoclonic epilepsy (OMIM PS254800)	AR AD	Can cause dementia or pseudodementia because of unrelenting seizures & anticonvulsant side effects
CLN5 CLN6 CLN8 PPT1 TPP1	CLN1 disease & CLN2 disease (neuronal ceroid lipofuscinoses [NCLs]) (OMIM PS256730)	AR	Phenotypes incl in NCLs that overlap w/AHS are CLN1 disease, classic infantile (previously classic infantile NCL, INCL, Santavuori-Haltia) & CLN2 disease, classic late infantile (previously late-infantile NCL, LINCL, Jansky-Bielschowsky disease)
COQ8A	COQ8A-related primary coenzyme Q₁₀ (CoQ₁₀) deficiency	AR	Epilepsia partialis continua has been described in some affected persons. ⁴ Targeted therapy: Persons w/primary CoQ₁₀ deficiency may respond well to high-dose oral CoQ₁₀ supplementation.
CTSA	Galactosialidosis (OMIM 256540)	AR	During infancy & early childhood, storage diseases can be assoc w/progressive encephalopathy w/primary involvement of cortical gray matter & refractory epilepsy.
DGUOK	Deoxyguanosine kinase deficiency (DGUOK deficiency)	AR	In contrast to POLG-related AHS, DGUOK deficiency is not characterized by seizures or brain imaging abnormalities.
DNA2	DNA2-related mtDNA maintenance defect	AD	PEO & PEO w/systemic involvement ⁵
FBXL4	FBXL4-related encephalomyopathic mtDNA depletion syndrome	AR	Early infantile encephalopathy, hypotonia, lactic acidosis, & mtDNA depletion ⁶
FOLR1	FOLR1-related cerebral folate transport deficiency	AR	Neonatal-onset progressive encephalopathy w/refractory seizures Targeted therapy: Oral administration of 5-formylTHF is usually sufficient to bring CSF folate levels into normal range for age.
HEXA	Hexosaminidase A deficiency	AR	During infancy & early childhood, storage diseases can be assoc w/progressive encephalopathy w/primary involvement of cortical gray matter & refractory epilepsy.
HEXB	Sandhoff disease	AR
MGME1	MGME1-related mtDNA maintenance defect	AR	Multisystemic mitochondrial phenotype w/PEO, emaciation, & respiratory failure
MPV17	MPV17-related mtDNA maintenance defect	AR	Multisystemic mitochondrial disease w/liver dysfunction, brain & peripheral nerve disease, gastrointestinal dysmotility, & lactic acidosis
MT-TK ⁷	MERFF ⁸	See footnote 9.	Multisystemic mitochondrial disorder characterized by myoclonus (often 1st symptom) followed by generalized epilepsy, ataxia, weakness, exercise intolerance, & dementia Onset can occur from childhood to adulthood, following normal early development Common findings are ptosis, hearing loss, short stature, optic atrophy, cardiomyopathy, cardiac dysrhythmias, & peripheral neuropathy
MT-TL1 ¹⁰	MELAS ^8, 11	See footnote 12.	Multisystemic mitochondrial disorder w/onset typically occurring in childhood Onset of symptoms is often ages 2-10 yrs. Most common initial symptoms are generalized tonic-clonic seizures, recurrent headaches, anorexia, & recurrent vomiting. Seizures are often assoc w/stroke-like episodes of transient hemiparesis or cortical blindness. The cumulative residual effects of the stroke-like episodes gradually impair motor abilities, vision, & mentation by adolescence or young adulthood. Sensorineural hearing loss is common.
NDUFS4	NADH coenzyme Q reductase deficiency (OMIM 252010)	AR	Epilepsia partialis continua has been described in some affected persons. ¹³
NEU1	Infantile sialidosis (OMIM 256550)	AR	During infancy & early childhood, storage diseases can be assoc w/progressive encephalopathy w/primary involvement of cortical gray matter & refractory epilepsy.
OPA1	Optic atrophy type 1 (OMIM 165500)	AD	Childhood-onset visual loss
PABPN1	Oculopharyngeal muscular dystrophy	AD	Progressive adult-onset myopathy w/ ptosis, dysphagia, & proximal weakness
PLPBP	PLPBP deficiency (pyridoxine-dependent epilepsy)	AR	Neonatal-onset progressive encephalopathy w/refractory seizures Targeted therapy: Pyridoxine is the first-line therapy. Most individuals have a favorable response to pyridoxine.
PNPO	PNPO deficiency (pyridoxine-dependent epilepsy)	AR	Neonatal-onset progressive encephalopathy w/refractory seizures Targeted therapy: ~60% of persons are resistant to pyridoxine & require treatment with pyridoxal 5'-phosphate; ~40% respond to pyridoxine alone.
POLG2	POLG2-related mtDNA maintenance defect	AD	Adult-onset PEO & multisystemic mitochondrial disease w/mtDNA depletion
RNASEH1	RNASEH1-related mtDNA maintenance defect	AR	PEO & multisystemic mitochondrial disease w/mtDNA depletion
RRM2B	RRM2B mtDNA maintenance defects	AR AD	Neonatal-onset hypotonia, lactic acidosis, & neurologic deterioration, w/ or w/o renal tubular dysfunction Adult-onset PEO, variable gastrointestinal dysmotility, multisystemic mitochondrial disease
SCN1A	SCN1A seizure disorders	AD	At the severe end of the spectrum, severe infantile epileptic disorder that appears progressive at onset but usually plateaus into developmental arrest/delay
SCN2A	SCN2A-related early infantile epileptic encephalopathy (OMIM 613721)	AD	Severe infantile epileptic disorder that appears progressive at onset but usually plateaus into developmental arrest/delay
SCO1	SCO1-related disorders (OMIM 603644)	AR	Infantile-onset multisystemic mitochondrial disease, Leigh-like syndrome w/cardiac hypertrophy & failure
SLC25A19	SLC25A19-related thiamine metabolism dysfunction (incl Amish lethal microcephaly & thiamine metabolism dysfunction syndrome 4)	AR	Targeted therapy: Oral thiamine treatment is critical from the time of diagnosis. This treatment is lifelong. It prevents metabolic decompensation & improves outcomes.
SLC25A4	SLC25A4-related mtDNA maintenance defect	AR	Primary presenting features are myopathy, hypertrophic cardiomyopathy, & ophthalmoplegia.
SLC46A1	Hereditary folate malabsorption	AR	Neonatal-onset progressive encephalopathy w/refractory seizures Targeted therapy: Early treatment w/oral 5-formylTHF or, preferably, the active isomer of 5-formylTHF (Isovorin^® or Fusilev^®) readily corrects the systemic folate deficiency &, if the dose is sufficient, can achieve CSF folate levels that prevent or mitigate the neurologic consequences of hereditary folate malabsorption.
SUCLA2	SUCLA2-related mtDNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduria	AR	Infantile encephalomyopathy, methylmalonic aciduria, epilepsy, hepatopathy, & cardiomyopathy
SUCLG1	SUCLG1-related mtDNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduria ¹⁴	AR
SUOX	Isolated sulfite oxidase deficiency	AR	Neonatal-onset progressive encephalopathy w/refractory seizures Usually present earlier in infancy than AHS
TBC1D24	TBC1D24-related disorders	AR ¹⁵	Epilepsia partialis continua has been described in some affected persons. ²
TK2	TK2-related mtDNA maintenance defect, myopathic form	AR	At the severe end of the spectrum, infantile-onset myopathy w/neurologic involvement & rapid progression to early death
TWNK	Autosomal dominant PEO, infantile-onset spinocerebellar ataxia, Perrault syndrome, & TWNK-related mtDNA maintenance defect ¹⁶	AR AD	Digenic inheritance of PEO has been reported in 2 persons w/double heterozygosity for a POLG pathogenic variant & a TWNK pathogenic variant. ¹⁷
TYMP	Mitochondrial neurogastrointestinal encephalopathy	AR	Cachexia, gastrointestinal dysmotility, peripheral neuropathy, PEO, leukoencephalopathy ¹⁸
Single large-scale mitochondrial DNA deletion ranging in size from 1.1 to 10 kb	Chronic progressive external ophthalmoplegia (CPEO) & Kearns-Sayre syndrome (KSS) (See Single Large-Scale Mitochondrial DNA Deletion Syndromes.)	See footnote 19.	CPEO in a simplex case or when there is a maternal family history can be the result of a large-scale single deletion of mtDNA that may only be detected in limited tissues (e.g., skeletal muscle). CPEO is sometimes complicated by mild proximal muscle weakness & dysphagia & can be considered to lie on a spectrum of disease from pure CPEO to KSS. ²⁰ A multisystemic disorder defined by the triad of onset age <20 years, pigmentary retinopathy, & PEO. In addition, persons have ≥1 of the following: cardiac conduction block, CSF protein concentration >100 mg/dL, or cerebellar ataxia. Onset is usually in childhood. PEO, characterized by ptosis, paralysis of the extraocular muscles (ophthalmoplegia), & variably severe proximal limb weakness, is relatively benign. ²¹

: 5-formytetrahydrofolate = 5-formylTHF; AD = autosomal dominant; AHS = Alpers-Huttenlocher syndrome; AR = autosomal recessive; ASM = anti-seizure medication; CSF = cerebrospinal fluid; GRACILE syndrome = growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death syndrome; MOI = mode of inheritance; PEO = progressive external ophthalmoplegia; XL = X-linked
1.: Genes are ordered alphabetically.
2.: Mameniškienė & Wolf [2017]
3.: Amadori et al [2022]
4.: Hikmat et al [2016]
5.: Ronchi et al [2013]
6.: Gai et al [2013]
7.: The m.8344A>G pathogenic variant in the mitochondrial gene MT-TK is present in more than 80% of affected individuals with typical findings. Pathogenic variants in MT-TF, MT-TH, MT-TI, MT-TL1, MT-TP, MT-TS1, and MT-TS2 have also been described in a subset of individuals with MERRF.
8.: Evidence to date suggests that diabetes and cardiomyopathy are not common in POLG-related disorders, distinguishing POLG-related disorders from other multisystemic mitochondrial diseases.
9.: MERRF is caused by pathogenic variants in mtDNA and is transmitted by maternal inheritance.
10.: The m.3243A>G pathogenic variant in the mitochondrial gene MT-TL1 is present in approximately 80% of individuals with MELAS. Pathogenic variants in MT-TL1 or other mtDNA genes, particularly MT-ND5, can also cause this disorder
11.: Hirano et al [1992]
12.: MELAS is caused by pathogenic variants in mtDNA and is transmitted by maternal inheritance.
13.: Antozzi et al [1995]
14.: Molaei Ramsheh et al [2020]
15.: Most TBC1D24-related disorders are inherited in an autosomal recessive manner.
16.: Peter & Falkenberg [2020]
17.: Van Goethem et al [2003a], Da Pozzo et al [2015]
18.: Pacitti et al [2018]
19.: SLSMDSs are almost never inherited, suggesting that these disorders are typically caused by a de novo single large-scale mitochondrial DNA deletion (SLSMD) that occurs in the mother's oocytes during germline development or in the embryo during embryogenesis.
20.: Some individuals with CPEO (<20%) have a pathogenic single-nucleotide variant of mtDNA (e.g., m.3243A>G).
21.: Most individuals with KSS have a common deletion of 4,977 nucleotides involving 12 mitochondrial genes.

From: POLG-Related Disorders

GeneReviews^® [Internet].

Adam MP, Feldman J, Mirzaa GM, et al., editors.

Seattle (WA): University of Washington, Seattle; 1993-2024.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.