Mitochondrial Conditions

Mitochondria - Overview

- makes 90% of our energy

- mtDNA has 37 genes with NO introns

- high mutation rate due to continuous replication

- complex II is entirely coded by nuclear genes

- exhibits maternal inheritance

- can be multiple within each cell and can very by cell and tissue type

Heteroplasmy

The presence of a mixture of mutant and WT mtDNA genomes within a cell

- can decrease as one gets older because selection against mutant mitochondria

Homoplasmy

The presence of identical mtDNA/mitochondrias within a cell

Threshold Effect

Specific heteroplasmic load for a specific mtDNA mutation that any given tissue tolerates before it shows signs of pathology (symptoms)

Bottleneck Effect

Rapid changes in heteroplasmy levels can be seen during oogenesis

- some offspring can receive all mutant, some mutant, little mutant, or no mutant mtDNA

Leigh Syndrome - Genes

>75 genes known to cause Leigh Syndrome

- mtDNA & nuclear DNA

- X-linked: PDHA1

- AR: SURF1

- Mito: mtATP6 (most common mito)

Leigh Syndrome - Symptoms

- Onset: 3 - 12 months (infancy)

- Leukodystrophy on MRI

- Developmental delays/Regression

- Optic atrophy, retinitis pigmentosa, *SALT & PEPPER retina*

- Ataxia, spasticity, hypotonia

- Neuropathy

- Nystagmus

- Ophthalmoparesis

- Dysphagia

- Hypertrophic cardiomyopathy

- Deafness

- Bilateral, symmetrical hyperintensities in basal ganglia on MRI

Leigh Syndrome - Diagnosis & Treatment

- People often not diagnosed until after have symptoms affecting their CNS

- Often triggered by illness

- Clinical diagnostic criteria available

- Supportive treatment

- Mito cocktail

- Monitor most things annually

Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) - Gene

- mt-ATP6 is most common

**high heteroplasmy level may cause Leigh Syndrome

Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) - Symptoms

- Onset: adolescence or young childhood

- developmental delays (with NO regression)

- numbness, tingling, or pain in extremities

- balance/coordination problems

- proximal muscle weakness

- vision loss, light sensitivity, retinitis pigmentosa (SALT & PEPPER retinopathy)

- hearing loss

- seizures

- cardiac conduction defects

*can have many years of stability between episodes of decline

Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) - Diagnosis & Treatment

- Clinical features & molecular testing

- Supportive treatment

- Mito cocktail

- Monitor most things annually

Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes (MELAS) - Gene

- 80% of cases have MT-TL1 (m.3243 A>G)

Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes (MELAS) - Symptoms

- Elevated lactic acidosis in blood, CSF

- Decreased NAA on MRI spectrometry

- Muscle weakness, exercise intolerance

- cortical vision loss

- hemiparesis

- vomiting

- hearing loss

- short stature

- diabetes

- peripheral neuropathy

- Stroke-like episodes (seizures, headaches, encephalopathy, dementia, psych)

- can present sporadically or after illness

- NO stroke findings on imaging

*Normal initial development prior to onset (2-40 y.o.)

Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes (MELAS) - Diagnosis & Treatment

- 2 sets of clinical diagnostic criteria published

- Molecular testing confirms and & establishes diagnosis

- Mito Cocktail may be beneficial to some

- Acute episode treatment: Arginine or L-Arg

- Long term treatment: Citrulline

Maternally Inherited Diabetes-Deafness (MIDD) - Genes

- 85% due to mt-TL1 (m.3243 A>G)

- Accounts for 1% of people with diabetes

- More common in Japan

Maternally Inherited Diabetes-Deafness (MIDD) - Symptoms

- Rapid & severe bilateral SNHL, typically in 20-30s

- Diabetes develops in 20s

- muscle cramps/weakness

- cardiac problems

- kidney disease

- short stature

Maternally Inherited Diabetes-Deafness (MIDD) - Diagnosis & Treatment

- Diagnosis can be made with genetic testing

- Treatment is symptomatic and monitoring manifestations

Myoclonic Epilepsy with Ragged Red Fibers (MERRF) - Genes

- >80% in MT-TK (m.8344A>G)

Myoclonic Epilepsy with Ragged Red Fibers (MERRF) - Symptoms

- Onset: childhood to adulthood

- myoclonus

- CNS deterioration -> seizures, ataxia, weakness, dementia, psych

- short stature

- cardiomyopathy, dysrhythmias

- hearing loss

- ophthalmoplegia, ptosis

- exercise intolerance

- peripheral neuropathy

- normal development into cognitive delays

- Inc. lactate & pyruvate in blood & CSF following exercise

- muscle biopsy has Ragged Red Fibers

Myoclonic Epilepsy with Ragged Red Fibers (MERRF) - Diagnosis & Treatment

- Clinical diagnosis: myoclonus, generalized epilepsy, ataxia, and ragged red fibers (RRF) in the muscle biopsy

- Diagnosis via molecular testing

- Mito Cocktail

- routine screenings every 6 - 12 months

- Annual neurologic, ophthalmologic, cardiology, endocrine

- Audiology every 2 to 3 years

Leber Hereditary Optic Neuropathy (LHON) - Genes

- MT-ND4 (75%)

- MT-ND6 (best visual outcome and chance for spontaneous recovery)

- MT-ND1

- Majority of individuals are homoplasmic

- 70% heteroplasmy load required for symptom presentation

- Most frequent mitochondrial disease

Leber Hereditary Optic Neuropathy (LHON) - Symptoms

- Onset: 15 to 35 years

- Strong MALE preponderance (80-90%)

- Typically presents with central vision loss that typically begins painlessly and in one eye. Occurs in 2nd eye within weeks or months (97% by one year)

- Neurological abnormalities are more common (postural tremor, peripheral neuropathy, movement disorders, etc.)

- most have vision loss <50 y.o.

- ganglion cell layer thins

- Low penetrance: 50% of males & 10% of females AFFECTED

Leber Hereditary Optic Neuropathy (LHON) - Diagnosis & Treatment

- No clinical criteria

- Dx made when have ocular findings AND PV in mtDNA

- No smoking or alcohol

- Assess vision, heart rhythm (EKG), and neuro signs

- No curative treatment

- Idebenone - skips complex II and restores ETC

- HRT - estrogen seems to be protective

- **Onset earlier (<20 yr) correlates with BETTER visual outcome**

Pearson, Kearns Sayre, & CPEO Syndromes - Genes

- Large mtDNA deletions

- almost always de novo

Pearson Syndrome - Symptoms

- Onset: Infancy/early childhood

- Death if very sick or severe Sx

- Sideroblastic anemia

- bone marrow failure

- exocrine pancreatic failure

- renal fanconi syndrome

- lactic acidosis

- body shutting down -> weakness, fatigue, frequent infections, easy bruising, FTT, liver/kidney failure

Pearson, Kearns Sayre, & CPEO Syndromes - Diagnosis & Treatment

- Dx based on large mtDNA deletions

- Treatment is supportive and monitoring symptoms

- Folinic acid supplementation for Kearns Sayre if deficient

- Mito Cocktail

Kearns Sayre Syndrome - Symptoms

- Onset: Childhood-adolescence

- Must live through infancy (not have Pearson) to develop this

- retinopathy, rod-cone dystrophy, ptosis, ophthalmoplegia

- cardiac conduction defects

- endocrine dysfunction (diabetes, hypothyroidism, adrenal insufficiency

- ataxia

- SNHL

- FTT

Chronic Progressive External Ophthalmoplegia (CPEO) - Symptoms

- Onset: Adolescence-adulthood

- can progressive from others (Pearson & Kearns Sayre) or present with either

- ptosis

- ophthalmoplegia

- proximal limb weakness

- exercise intolerance, myopathy, dysphagia

- CPEO+ = SNHL, neuropathy, ataxia, parkinsonism

Mitochondrial Neurogastrointestinal Encephalopathy Disease (MNGIE) - Gene

- Nuclear gene

- TYMP

- AR inheritance

Mitochondrial Neurogastrointestinal Encephalopathy Disease (MNGIE) - Symptoms

- Onset: Avg 18 y.o. but variable

- Dysmotility -> nausea, dysphagia, reflux, pain, diarrhea, emesis (1st signs)

- Cachexia (wasting or severe, unintentional weight loss & muscle wasting)

- ptosis, ophthamoplegia, ophthalmoparesis

- leukoencephalopathy

- demyelinating peripheral neuropathy

- distal weakness

Mitochondrial Neurogastrointestinal Encephalopathy Disease (MNGIE) - Diagnsosi & Treatment

- genetic testing biallelic PV in TYMP

- elevated plasma thymidine & deoxyuridine

- enzymatic analysis of thymidine phosphorylase

- treatment is symptomatic

Sengers Syndrome - Gene

- AGK

- AR inheritance

Sengers Syndrome - Symptoms

- Hypotonia

- Hypertrophic cardiomyopathy

- Cataracts

- Muscle weakness & lactic acidosis after exercise

- NORMAL cognition

Pyruvate Dehydrogenasae Deficiency - Gene

- PDHA1

- PV in this gene can lead to Leigh Syndrome

Pyruvate Dehydrogenasae Deficiency - Symptoms

- lactic acidosis

- developmental delay

- neurologic problems

- hypotonia