2. ‫خدا‬ ‫بنام‬

3. Pearson Syndrome
NARP
F. Mahvelati MD.
Child Neurologist

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

5. 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.

6. 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.

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

8. 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.

9. 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.

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

11. 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.

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

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

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

15. 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.

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

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

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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)

25. 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).

26. 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.

27. 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.

28. 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.

29. 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.

30. 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.

31. 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.

32. 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.

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

34. Our Time is up!