Mitochondrial

GRACILE syndrome

• Mechanism of disease: BCS1L; autosomal recessive. De novo rate: not typically emphasized for AR (parents are usually carriers).

• Clinical features: Growth restriction, aminoaciduria, cholestasis/liver failure, iron overload, lactic acidosis, early death.

• Diagnosis / Work-up: Clinical picture of neonatal/infantile multisystem mitochondrial disease + molecular confirmation of biallelic BCS1L pathogenic variants.

• Management: Supportive/ICU-level management (metabolic crises, liver/kidney failure), multidisciplinary care. Prognosis is poor.

Leber Hereditary Optic Neuropathy (LHON)

• Mechanism of disease: mtDNA variants classically in MT-ND genes (e.g., m.11778G>A); mitochondrial (maternal) inheritance with incomplete penetrance; de novo mtDNA variants can occur but many are maternally transmitted.

• Clinical features: Painless subacute central vision loss, often young adult onset; male predominance.

• Diagnosis / Work-up: Clinical optic neuropathy + ophthalmologic testing; confirm with mtDNA testing for known LHON variants.

• Management: Avoid triggers (e.g., smoking/excess alcohol often discussed in LHON counseling), visual rehabilitation/low-vision supports; specialty-directed therapy where appropriate.

Leigh syndrome

• Mechanism of disease: Genetically heterogeneous. Can be nuclear gene--encoded Leigh syndrome spectrum (many nuclear genes; multiple inheritance patterns depending on gene) and mtDNA-associated Leigh syndrome spectrum (maternal). "De novo rate" varies by gene/mechanism and is not uniform.

• Clinical features: Infantile onset neurodegeneration with developmental regression, brainstem/basal ganglia involvement, lactic acidosis, and episodic decompensation.

• Diagnosis / Work-up: Clinical + neuroimaging consistent with Leigh + metabolic evidence (elevated lactate) + genetic confirmation (nuclear panel/exome + mtDNA testing depending on presentation).

• Management: Primarily supportive and crisis prevention: avoid metabolic stressors; treat acidosis/seizures; organ-specific care (cardiac, renal, hepatic); multidisciplinary follow-up.

NARP syndrome

• Mechanism of disease: Most commonly mtDNA MT-ATP6 variants; mitochondrial (maternal) inheritance with heteroplasmy; de novo mtDNA variants can occur.

• Clinical features: Neuropathy, ataxia, retinitis pigmentosa; variable onset and severity depending on heteroplasmy.

• Diagnosis / Work-up: Clinical phenotype consistent with NARP + mtDNA testing (often MT-ATP6) and heteroplasmy assessment; evaluate multisystem involvement.

• Management: Symptomatic treatment (vision supports, neuropathy/ataxia management, seizure care if present) + monitoring for systemic complications.

MELAS syndrome

• Mechanism of disease: Usually mtDNA variant m.3243A>G (MT-TL1) (most common); mitochondrial (maternal) inheritance with heteroplasmy; de novo possible.

• Clinical features: Stroke-like episodes, seizures/encephalopathy, exercise intolerance, headaches/vomiting, hearing loss, short stature, multisystem disease.

• Diagnosis / Work-up: Clinical diagnosis (stroke-like episodes with characteristic imaging not confined to vascular territories) + metabolic findings + mtDNA testing.

• Management: Multidisciplinary supportive care; seizure management; management of stroke-like episodes and systemic complications; tailored surveillance.

MERRF syndrome

• Mechanism of disease: Frequently mtDNA MT-TK variant; mitochondrial (maternal) inheritance with heteroplasmy; de novo possible.

• Clinical features: Myoclonic epilepsy (prominent), seizures, progressive neurologic impairment; multisystem involvement possible.

• Diagnosis / Work-up: Clinical phenotype + EEG/neuro eval + supportive muscle/biopsy findings may be used historically; confirm with mtDNA testing.

• Management: Seizure management by neurology, supportive therapies, and screening/treatment of systemic manifestations.