Leigh's Disease
Diseases

Valentina Gentile e Chiara Colaci

DEFINITION:

Leigh's disease, also known as Subacute Necrotizing Encephalomyelopathy, is a rare neurometabolic disorder that affects the CNS. It is named by Denis Archibald Leigh, a British psychiatrist who first described the condition in 1951.It’s a progressive disease,there are also different isoforms, and it’s characterized by specific neuropathologic signs due to secondary lesions placed in brainstem and basal ganglia.

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Leigh's disease

EPIDEMIOLOGY:

It is an inherited disorder that usually affects infants between the age of three months and two years, but, in rare cases, teenagers and adults as well. In details, it’s a mithocondrial disease and it can be a familiar or sporadic disorder. Prevalence at birth is 1/36000 and, unfortunately, death is premature, within a few years, but some milder cases have survive to the mid-teens(generally,alterations cause death in one or two years after birth).

SYMPTOMS:

Neurological symptoms generally start unexpectedly or in a subacute mode, and,sometimes, are increased by fever,surgical treatment or aspecific infections.
Evidences in infants:

• loss of head control and motor skills
• hypokinesia
• poor sucking ability
• loss of appetite
• vomiting
• irritability, continuous crying
• seizures
• tics and myoclonus

If symptoms become evident during the age of 2 years, there are also:

• movement disorders (Cytochrome c oxidase partial deficiency-associated Leigh disease presenting as an extrapyramidal syndrome,2001)
• ataxia (Ataxias with autosomal, X-chromosomal or maternal inheritance,2009)
• disarthria
• developmental regression(psychological and motorial)
• respiratory disorders: iperventilation, apnea, gasping (Hypoxic and hypercapnic challenges unveil respiratory vulnerability of Surf1 knockout mice, an animal model of Leigh syndrome,2011)
• Ocular disorders: oftalmoplegy, look alterations, nystagmus
• lactic acidosis can lead to impairment of respiratory and kidney function
• Deglutition troubles(paralysis)
• Dystonia
• Rigidity, tremor, corea

In some case are damaged peripherial nervers, so there are these symptoms:

• Areflexia
• Weakness
• Atrophy
• Decreased velocity conduction
• Autonomic failure

If the disease progresses in adults, it may also cause:

• general weakness
• kidney failure
• heart problems

Clinical evidences in other affected parents could change secondary to the genetic disorder:

• If a nuclear gene is modified,parents affected show signs and symptoms which are similar to the proband ones.
• The X-linked Leigh’s disease (due to PDH mutation E1’)develops above all in male, who may show a similar serious phenotype.
• Patients with autosomal recessive (in nuclear genes) Leigh’s syndrome’s form, show similar phenotype to the other family members with disease.
• In the Leigh’s disease due to mtDNA eteroplasmic mutation, there are also variable clinical evidences between maternal parents; in fact symptoms include: retinitis pigmentosa,oftalmoplegy, optic atrophy, ataxy, simil-stroke episodes,epilepsy, movement disordes, behaviour trouble,short everage etc.

DIAGNOSIS:

Laboratory test:

Metabolic test:

• aminoacid screening(in blood sample) may show aspecific aminoaciduria
• possibile increased of: lattato(liquor or blood), urinary or sieric piruvato and other molecs with a role into TCA’s cycle (es. '-chetoglutarato, citrato, succinato, ecc.). Remember: PDH activity can be examinated on leucocytes or cutaneous fibroblasts in colture.Oxidative fosforilation, instead, can be studied on muscular cells or epathocytes.
• possible increased of: Ala and other aa whit a role in TCA cycle.(es. glutamato).
• Other test include evaluation of: sieric biotinidase , ematic long chain fatty acids,eritrocitary catalasys,and pipecolic acid(dd for perossisomal diseases).
• Etiological diagnosis is based on biochemical test for troubles in energetic production.

EEG:

• Multifocal encephalopaty

Radiology:

Diagnosis is based on brain imaging, which demonstrates specific lesions in brainstem and basal ganglia and, sometimes, in association, leucodystrophy and cerebral atrophy
NMR: Seq. T2: simmetric areas with increased intensity in brainstem, cerebellum and basal ganglia.
Nuclear MR Spettrometry(if possible): Decreased of Creatinphosphate/phosfate fraction in sick areas. Specific aetiology can be searched with an enzymatic analisys for COX and with a measurment of PDHC activity in cutaneous fibroblasts in colture and/or in muscular biopsy .Muscular Biopsy is made to evaluate mtDNA.

Histopathology:

Muscular Biopsy:

• histochemical analisys:alterations in fibers’ dimensions and abnormalities in mitochondrial ultrastructure.
• evaluation of: deficit in oxidative phosphorylation
• enzimology in colture cell,linphocytes and fibroblasts: specific troubles in PDH, Piruvato carboxilasys and I, IV or V complex.

Genetic test:

Genetic counselling is based on identification of disease’s causes.Search for:

• mtDNA mutation for sporadic cases or maternal derivation ones.
• nDNA mutation above all in genes of I,II and IV genetic complex,E1’ PDH’s subunit..

Prenatal diagnosis and prevention:

• Is possibile in case of nuclear genes identification.
• Is difficult when only biochemical alteration is known, because of technical difficulties in amniocytes’s analisys and in identification of different mutation in fibroblasts.
• Prenatal Diagnosis of mtDNA is difficult for the important mtDNA’s eteroplasmia and histological typical elements. There aren’t guide lines for Leigh’s disease ‘s prenatal diagnosis. Literature suggests cases in which prenatal diagnosis could be useful to research specific mtDNA’s mutations (T8993 G/C) with classic biomolecular methods or microsatellite DNA.But informations about this contest are not enough available.

PATHOGENESIS:

Leigh disease ,that usually begins in early childhood,is caused by genetic mutations which result in mitochondrial dysfunction and this causes a chronic lack of energy in the cells, which, in turn, affects the central nervous system and inhibits motor functions.
Mitochondria are the energy factories of the cells, which convert energy of glucose and fatty acids into a substance called Adenosine triphosphate (ATP);the energy stored in the ATP is then used to perform almost all of the cell’s metabolic functions. Mitochondria also carry its own DNA, called mitochondrial DNA (mtDNA) that produces several of the enzymes essential to the production of ATP.
When irregular mutations take place in the mitochondrial DNA, the mitochondria become fail to function properly and the person is at risk for a number of disorders, including Leigh's disease.
The majority of patients with mitochondrial disease have significant neuropathology, with the most common features being spongiform degeneration, neuronal loss and gliosis. Although there is considerable overlap between different mitochondrial diseases, the nature and distribution of the lesions is sufficiently distinctive in some cases to suggest a specific diagnosis, on the other hand, a number of different defects in cerebral energy metabolism are associated with common patterns of neuropathology,as Leigh syndrome, suggesting that there is a limited range of responses to this type of metabolic disturbance.
There are many descriptions of neuropathological changes in patients with mitochondrial disease, but there has been remarkably little investigation of the underlying pathogenic mechanisms: Comparisons with other conditions of cerebral energy deprivation such as ischaemia/hypoxia and hypoglycaemia suggest a possible role for excitotoxicity initiated by excitatory amino acid neurotransmitters;an additional contributing factor may be peroxynitrite, which is formed from nitric oxide and the oxygen free radicals which accumulate with defects of the mitochondrial electron transport chain.

Mitochondrial diseases are often characterized by episodes of neurological dysfunction precipitated by intercurrent illness; depending on the severity of the metabolic abnormality, each of these episodes carries a risk of further neuronal death and the result is usually progressive accumulation of irreversible damage. The balance between reversible functional impairment and neuronal death during episodes of metabolic imbalance is determined by the effectiveness of various protective mechanisms which may act to limit the damage. These include protective metabolic shielding of neurons by astrocytes and suppression of electrical activity (and hence energy demands) by activation of ATP-gated ion channels.
In addition, recent evidence suggests that lactic acid, the biochemical abnormal element common to these conditions, may not be toxic at moderately high concentrations but may in fact be protective by reducing the sensitivity of neurons to excitotoxic mechanisms.
Therefore abnormal brain function is a major manifestation of the majority of disorders of mitochondrial energy metabolism (Effect of Peroxynitrite on the Mitochondrial Respiratory Chain: Differential Susceptibility of Neurones and Astrocytes in Primary Culture,1995) and the neurological features of these diseases are extremely diverse and are associated with a correspondingly wide range of pathological changes. Defects have been defined in enzymes of the mitochondrial matrix and in components of the electron transport chain in the inner mitochondrial membrane and, as these all involve the central common pathways of energy generation in the cell, it is not surprising that there is considerable overlap in structural and functional abnormalities in the different conditions.
There are many others enzymes defects,in others parts of organism, involving individual pathways of substrate oxidation in the mitochondria in which there may be remarkably little permanent structural damage to the brain, but the repeated episodes of metabolic cause intermittent accumulation of toxic or reduced supply of metabolizable substrate and the damage of tissues.

PATIENT RISK FACTORS:

GENETIC

In Leigh's disease, crucial cells in the brain stem have mutated mtDNA (Mitochondrial DNA-Associated Leigh Syndrome and NARP GeneReviews,2003), creating poorly functioning mitochondria and this causes a chronic lack of energy in the cells, which, in turn, affects the central nervous system and inhibits motor functions.
At least 26 defects have been identified in Leigh’s syndrome and they include:

• One of the most important mutation of mtDNA or in nuclear DNA is located at gene SURF1 (Mutations in the SURF1 gene associated with Leigh syndrome and cytochrome C oxidase deficiency,2001)that encodes a protein localized to the inner mitochondrial membrane and thought to be involved in the biogenesis of the cytochrome c oxidase complex or COX assembly factors or Respiratory Chain Complex. The protein is a member of the SURF1 family (Analysis of Leigh syndrome mutations in the yeast SURF1 homolog reveals a new member of the cytochrome oxidase assembly factor family,2010), which includes the related yeast protein SHY1 and rickettsial protein RP733.The gene is located in the surfeit gene cluster, a group of very tightly linked genes that do not share sequence similarity, where it shares a bidirectional promoter with SURF2 on the opposite strand. Cytochrome c oxidase subunit I or COX1 is a critical component of one of the enzymes in the energy production pathway in cells, and disruptions in COX1 production, lead to loss of enzyme activity and the symptoms in Leigh Syndrome. Using molecular biological techniques and DNA analysis, the researchers were able to pin point a mutation in the TACO1 gene which encodes a translational activator important for the proper production of a protein called COX1. This study is also the first to identify a protein of this nature in humans.

• The mutation in the oxidative phosphorylation enzymes,which are on both the mtDNA and the nuclear DNA,is a typical mutation of the X-linked Leigh's syndrome.The gene mutated, located on the X chromosome ,encoding PDHA1, which encodes the E1alpha subunit that is a part of the pyruvate dehydrogenase complex that is complex of three enzymes that transform pyruvate into acetyl-CoA by a process called pyruvate decarboxylation.This genetic mutations occur on the X female chromosome; males have one X chromosome and one Y chromosome, so a mutated gene on the X chromosome is enough to cause leigh syndrome. Females have two X chromosomes, so a mutated gene on one X chromosome generally have less effect on a woman because of the non-mutated copy of the same gene on the other X chromosome.A woman with a gene mutation on one X chromosome will be a carrier (Maternally-inherited Leigh syndrome-related mutations bolster mitochondrial-mediated apoptosis,2004). On average, 50% of her sons will inherit the mutation and develop leigh syndrome, and 50% of her daughters will inherit the mutation and become a carrier.

• Dihydrolipoamide dehydrogenase deficiency

• Biotinidase deficiency

• Mutations in NUP62, encoding a component of the nuclear pore that create infantile bilateral striatal necrosis and the transmission of this mutation is autosomal recessive

• Acute necrotizing encephalopathy, which may be triggered by viral infections. Recently mutations in RANBP2, encoding another nuclear pore component, have been linked to infection-triggered familial acute necrotizing encephalopathy .

There are different genetic desease’s isoforms, so there are different ways can be inherited the different types of mutations in Leigh’s syndrome:

• By autosomal recessive transmission. When both parents carry the gene, there is a 25 per cent chance that each child may be affected. For example Respiratory Chain Complex’s gene mutation
• By X linked transmission. Boys can inherit it from a mother who carries it. Daughters may inherit the carrier status. For example oxidative phosphorylation enzymes’s gene mutation
• By maternal transmission, the mother may be affected and all children are at risk of inheriting the gene. Maternal mitochondrial inheritance is a subtype of Leigh syndrome and is caused by mutations in at least 11 genes of mitochondrial DNA This condition has an inheritance pattern known as MILS
• It may also occur sporadically.

TISSUE SPECIFIC RISK FACTORS:

Physiopathological (due to tissue function and activity): crucial cells in the brain stem have mutated mtDNA, creating poorly functioning mitochondria

COMPLICATIONS:

Even if death is premature, during the progression of the disease may develop serious illnesses related to:

• Cerebellar syndrome with movement disorders:atassia (Disorders of movement in Leigh syndrome, 1993)
• Retinitis pigmentosa
• Pyruvic acid levels raised with respiratory disease
• Cranial nerve disorder
• Lactic acidosis e nefropathy

THERAPY:

Leigh's disease is an extremely rare disorder, and there is currently no cure that is effective in slowing the progression of Leigh disease; So the treatment for Leigh's syndrome is limited ,only partially effective based on maintaining function for as long as possible is the primary focus rather than recovery. Treatment is aimed at easing the disease-related symptoms and involves neurologists, pediatricians, clinical geneticists, nurses, and other related caretakers and consists of:

• thiamin orally mg/die, helps to temporarily correct some complications of metabolic disorders and lactic acidosis associated with pyruvate carboxylase deficiency (Beneficial effect of pyruvate therapy on Leigh syndrome due to a novel mutation in PDH E1α gene,2011 and Pyruvate therapy for Leigh syndrome due to cytochrome c oxidase deficiency,2010) and hyperalaninemia. You should try a course of therapy of at least 2 months to assess the therapeutic efficacy, although this approach is difficult to estimate the genetic and phenotypic heterogeneity of these diseases
• You can also try coenzyme Q10 (Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations,2006), vitamin K and vitamin C
• A low-carbohydrate diet may be recommended to diet tailored to the individual patient especially to individuals who have the X-linked form; vitamins and cofactors as indicated, and physical , occupational and speech therapy
• Oral sodium bicarbonate or sodium citrate may also be prescribed to manage lactic acidosis.
• dichloroacetate 15 a 200 mg/kg, that is recently approvated from FDA for the treatment of children with sustained lactic acidemia. Our trial of DCA is underway. Some children with Leigh's syndrome do not have elevated blood lactate levels but do have elevated levels in their cerebrospinal fluid allowing them to be treated. In some cases, lactate levels are not high enough to warrant treatment. DCA (Dichloroacetate therapy in Leigh syndrome with a mitochondrial T8993C mutation,2002) adds to the list of treatments for the metabolic consequences of mitochondrial disease
• Drug treatments may be needed for seizure control, movement disorder, cardiac or renal complications.
• Only gene therapy offers the possibility of a cure and we at the Leigh's Center along with many scientists around the world are working hard to develop gene therapy for mitochondrial diseases.
  As of early 2004, there are no clinical trials to treat or cure Leigh syndrome;However, studies are underway to better understand all mitochondrial diseases in an effort to identify treatments and, eventually, a cure.
• Psychological counseling and support for family members caring for a child with Leigh disease is often encouraged
• Physical therapists often assist in exercises designed to maintain strength and range of motion. As the disease progresses, occupational therapists can provide positioning devices for comfort.
• The management of symptomatic and supportive measures include nasogastric tube or gastrostomy feeding problems in order to prevent aspiration, tracheostomy and ventilatory support for respiratory failure, early treatment of infections.