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Pearson Syndrome NARP F. Mahvelati MD. Child Neurologist

Pearson Syndrome Pearson marrow-pancreas syndrome was first described in 1979. Less than 100 cases have been reported worldwide. Both sexes are affected

Pearson Syndrome The majority of cases are sporadic, although more rarely familial cases do occur, which can be maternally or autosomally inherited. It can result from either deletion or combined duplication/deletion mutations.

Pearson Syndrome The specific mtDNA deletion includes deletion of the complete genes for ATPases 6 and 8, cytochrome c oxydase III, and NADH dehydrogenase 3, 4, 4L and 5.

Pearson Syndrome mtDNA deletions impair mitochondrial protein synthesis due to the loss of tRNA genes.

Pearson Syndrome It is characterised by a sideroblastic anaemia with vacuolisation of marrow precursors, accompanied by neutropenia, thrombocytopenia, exocrine pancreatic dysfunction and abnormal liver function, but neurological symptoms.

Pearson Syndrome Neonates may be well at birth, but some 40% of patients present in the first year with persistent hypoplastic anemia, other cytopenias, low birth weight, microcephaly, and multiple organ system involvement (GI, neuromuscular, and metabolic). Hydrops fetalis has also been reported. Anemic newborns may need transfusion.

Pearson Syndrome During infancy and early childhood, failure to thrive, chronic diarrhea, and progressive hepatomegaly often occur.

Pearson Syndrome Episodic crises characterized by somnolence, vomiting, electrolytic abnormalities, lactic acidosis (elevated lactate:pyruvate ratio), and hepatic insufficiency. The lactic acidosis may become persistent with time.

Pearson Syndrome persistent or intermittent lactic acidemia, which is caused by defects in oxidative phosphorylation.

Pearson Syndrome Other organs can be affected, either simultaneously or during the course of the disease.

Pearson Syndrome Hepatic involvement may cause increases in transaminase, bilirubin, and lipid levels, as well as in steatosis. Some patients develop hepatic failure.

Pearson Syndrome Renal involvement is common and manifests as a tubulopathy, such as Fanconi syndrome. Endocrinologic disturbances, such as growth hormone deficiency, hypothyroidism, and hypoparathyroidism, may develop but are not usually part of the initial presentation.

Pearson Syndrome The endocrine pancreas usually remains functional; however, a few patients develop diabetes mellitus and adrenal insufficiency. Splenic atrophy Impaired cardiac function

Characteristic vacuolization of a hematopoietic precursor in the bone marrow. (Light microscopy; Wright-Giemsa stain)

Pearson Syndrome It is diagnosed by the presence of a single large scale rearrangement of mtDNA, as observed in Southern blot hybridization analysis of blood DNA. Southern blot or long-range PCR for the detection of mtDNA rearrangement is recommended.

Pearson Syndrome Death often occurs before the age of three years, due to metabolic crisis with lactic acidosis, bacterial sepsis due to neutropenia, or hepatocellular failure.

Pearson Syndrome Patients who survive early infancy typically undergo phenotypic evolution: Hematological manifestations spontaneously resolve, Neurological and myopathic signs either appear or worsen. Some patients develop typical KSS with ophthalmoplegia, ataxia, pigmentary retinitis, cardiac conduction defects and myopathy.

Neuropathy, ataxia, and retinitis pigmentosa (NARP); maternally inherited Leigh syndrome (MILS) NARP is a maternally transmitted multisystem disorder of young adult life comprising, in various combinations.

Neuropathy, ataxia, and retinitis pigmentosa (NARP); maternally inherited Leigh syndrome (MILS) It is characterized by developmental delay, seizures, proximal neurogenic muscle weakness, ataxia, dementia, sensory neuropathy, and retinitis pigmentosa.

Neuropathy, ataxia, and retinitis pigmentosa (NARP); maternally inherited Leigh syndrome (MILS) MILS is a multisystem degenerative encephalopathy with onset in infancy, characterized by hypotonia, myoclonus, brainstem dysfunction, peripheral neuropathy, developmental delay, psychomotor regression, ataxia, seizures, and optic atrophy.

Neuropathy, ataxia, and retinitis pigmentosa (NARP); maternally inherited Leigh syndrome (MILS) In 90% of NARP cases, It is associated with a Complex V: T8993G point mutation (mutation resulting in the replacement of a leucine by arginine) in the ATPase 6 gene (MTATP6; subunit 6 of complex V)

Neuropathy, ataxia, and retinitis pigmentosa (NARP); maternally inherited Leigh syndrome (MILS) When the percentage of mutant mtDNA is >95%, patients show the clinical, neuroradiological and neuropathological findings of maternally inherited Leigh’s syndrome (MILS).

Neuropathy, ataxia, and retinitis pigmentosa (NARP); maternally inherited Leigh syndrome (MILS) Brain MRI has revealed the presence of moderate, diffuse cerebral and cerebellar atrophy, and, in the most severely affected patients, symmetric lesions of the basal ganglia.

Neuropathy, ataxia, and retinitis pigmentosa (NARP); maternally inherited Leigh syndrome (MILS) Brain MRI has revealed the presence of moderate, diffuse cerebral and cerebellar atrophy, and, in the most severely affected patients, symmetric lesions of the basal ganglia.

Neuropathy, ataxia, and retinitis pigmentosa (NARP); maternally inherited Leigh syndrome (MILS) Brain MRI has revealed the presence of moderate, diffuse cerebral and cerebellar atrophy, and, in the most severely affected patients, symmetric lesions of the basal ganglia.

Neuropathy, ataxia, and retinitis pigmentosa (NARP); maternally inherited Leigh syndrome (MILS) The diagnosis can be confirmed by the characteristic pathological findings of symmetric necrotic foci in the thalamus, basal ganglia, brainstem, and dentate nuclei.

Neuropathy, ataxia, and retinitis pigmentosa (NARP); maternally inherited Leigh syndrome (MILS) The diagnosis can be confirmed by the characteristic pathological findings of symmetric necrotic foci in the thalamus, basal ganglia, brainstem, and dentate nuclei.

Neuropathy, ataxia, and retinitis pigmentosa (NARP); maternally inherited Leigh syndrome (MILS) Retinitis pigmentosa, present in about half of MILS patients, is a distinguishing clinical feature.

Neuropathy, ataxia, and retinitis pigmentosa (NARP); maternally inherited Leigh syndrome (MILS) Muscle fibers are COX positive, but a subset of fibers may be either negative or deficient for mitochondrial ATPase.

RRFs are consistently absent in the muscle biopsy. Neuropathy, ataxia, and retinitis pigmentosa (NARP); maternally inherited Leigh syndrome (MILS) RRFs are consistently absent in the muscle biopsy.

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