Download Neuropathy, ataxia and retinitis pigmentosa (NARP)

Neuropathy, ataxia and retinitis pigmentosa (NARP)
syndrome
Authors: Doctors Filippo M. Santorelli, MD1 and Alessandra Tessa, PhD
Creation Date: April 2004
Scientific Editor: Doctor Enrico Bertini
1
Unit of Molecular Medicine, Children’s Hospital "Bambino Gesù", P.zza S.Onofrio, 4, 00165 Rome, Italy.
mailto:[email protected]
Abstract
Keywords
Disease name and synonyms
Diagnostic criteria/definition
Differential diagnosis
Etiology
Clinical description
Diagnostic methods
Genetic counseling
Prenatal diagnosis
Management
Unresolved questions
References
Abstract
The syndrome of Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) is clinically heterogeneous but it
is often characterized by a combination of sensory-motor neuropathy, cerebellar ataxia, and night
blindness. Its prevalence is approximately estimated at 1:12 000. NARP usually presents in young adults.
Clinical presentation includes a combination of the following symptoms: early salt and pepper retinopathy;
retinitis pigmentosa; sluggish pupils; nystagmus; blindness; proximal muscle weakness; developmental
delay; corticospinal tract atrophy; dementia; hearing loss; seizures; ataxia; sensory neuropathy; proximal
neurogenic muscle weakness. A maternally inherited condition, the NARP syndrome is associated with
the 8993T>G mutation in the mtDNA gene, MTATP6, coding for the subunit ATPase 6. The 8993T>G
mutation results in an amino acid change from a highly conserved leucine 156 to arginine (L156R) and
leads to a severe impairment of the synthesis of mitochondrial ATP, reducing cellular energy and cell
death, particularly in tissues highly dependent upon the oxidative phosphorylation metabolism, such as
brain and retina. This mutation is also retrieved in 8-10% of Leigh disease, which in this case is
conventionally defined with the acronym MILS (maternally-inherited Leigh syndrome). Thus, MILS
represents the most severe phenotypic presentation of the NARP syndrome and it usually manifests in
subsequent affected generations resembling pseudo-anticipation. Treatment is only supportive.
Antioxidants have been recently proposed as helpful on the basis of experimental “in vitro” evidences.
Keywords
NARP, Neuropathy, Ataxia, and Retinitis Pigmentos, MLIS, mtDNA; MTATP6 gene; 8993T>G
transversion mutation.
Disease name and synonyms
Neuropathy, Ataxia, and Retinitis Pigmentosa
(NARP)
Diagnostic criteria/definition
The NARP syndrome is clinically heterogeneous
but it is often characterized by a combination of
sensory-motor neuropathy, cerebellar ataxia,
and night blindness. Laboratory investigations in
skeletal muscle are often negative. A maternally
Santorelli FM and Tessa A. Neuropathy, ataxia and retinitis pigmentosa (NARP) syndrome. Orphanet Encyclopedia. April 2004.
http://www.orpha.net/data/patho/GB/uk-NARP.pdf
1
inherited condition, the NARP syndrome is
associated with a point mutation at nucleotide
8993 in the mitochondrial (mt)DNA gene coding
for ATPase 6 of mtDNA.
Differential diagnosis
Approximately 10-20% of patients with Leigh
syndrome carry either the T8993G or T8993C
MTATP6 mutation. In such cases, patients are
better defined as having maternally-inherited
Leigh (MILS) syndrome and differ from typical
NARP patients by the presentation of a more
aggressive and lethal neurodegenerative
disorder.
In sporadic cases, differential diagnosis should
consider the rare autosomal recessive Refsum’s
disease, which is usually ruled out by the failure
to demonstrate elevated serum phytanic acid
levels. Cockayne’s syndrome is a condition that
should be easily recognisable because of
microcephaly, dwarfism, and a distinctive
physiognomy. In addition, death often occurs in
childhood.
The neurological features of Bassen-Kornzweig
usually do not include deafness. Acanthocytosis
in blood and the absence of betalipoproteins are
Usher’s
other
distinctive
manifestations.
syndrome is a genetically heterogeneous
disorder usually characterized by congenital
deafness, but cases with a more progressive
evolution have been described. Retinitis
pigmentosa, deafness, ataxia, and mental
retardation may also occur in rare cases of
spinocerebellar disorder, in Hallgren’s syndrome,
or in neurological complication of lipidosis.
However, presence of a congenital and usually
profound deafness or evidence for myoclonus
epilepsy are commonly found.
Etiology
The NARP syndrome is maternally transmitted
and is associated with a T-to-G point mutation at
nucleotide 8993 in the mtDNA gene, MTATP6,
coding for the subunit ATPase 6. The 8993T>G
mutation results in an amino acid change from a
highly conserved leucine 156 to arginine
(L156R) and leads to a severe impairment of the
synthesis of mitochondrial ATP, reducing cellular
energy and cell death, particularly in tissues
highly
dependent
upon
the
oxidative
phosphorylation metabolism, such as brain and
retina. The 8993T>G transversion is retrieved in
about 75% of patients. Two other MTATP6
mutations, 8993T>C [Santorelli et al., 1994] and
9176T>C [Thyagarajan et al. 1995] may also
occur less commonly.
Furthermore, NARP patient are frequently
observed among maternal relatives of infants
suffering from MILS in association with mtDNA
mutations in the MTATP6 gene. MILS can be
associated with other MTATP6 mutations,
including the 8993T>C and the 9176T>G
transversions [Carrozzo et al., 2001].
Clinical description
NARP usually presents in young adults. Clinical
presentation includes a combination of the
following symptoms: early salt and pepper
retinopathy; retinitis pigmentosa; sluggish pupils;
nystagmus;
blindness;
proximal
muscle
weakness; developmental delay; corticospinal
tract atrophy; dementia; hearing loss; seizures;
ataxia; sensory neuropathy; proximal neurogenic
muscle weakness. Lactic acidosis is rare in
NARP patients. There is no histochemical
evidence of mitochondrial myopathy. The
activities of the respiratory chain complexes in
muscle are usually normal.
The index case in the family, which was first
described [Holt et al., 1990], was a 47-year-old
female who developed night blindness at the age
of 12 years and was diagnosed as having
retinitis pigmentosa. She was blind by age 30. At
the age of 24 years, she had a generalized
seizure. In her early 30’s, she suddenly noticed
unsteadiness on walking which subsequently
progressed; there had been no evidence of
anticonvulsant toxicity. Sensory action potentials
were reduced in amplitude, indicating an axonal
sensory neuropathy. Quadriceps-muscle biopsy
showed mild chronic partial denervation with
collateral reinnervation.
Kerrison et al. (2000) described the progression
of retinopathy in NARP syndrome due to the Tto-G point mutation at the mtDNA nucleotide
position 8993 in the MTATP6 gene. Prior to the
onset of visual field constriction, ophthalmoscopy
revealed salt-and-pepper retinopathy. After the
visual fields had become constricted, fundus
examination showed diffuse peripheral bone
spicule formation, optic nerve pallor, and
arteriolar attenuation consistent with retinitis
pigmentosa. Porto et al. (2001) reported an
otherwise healthy 42-year-old woman with
isolated
late-onset
cone-rod
dystrophy
characterized by difficulty driving at night
beginning at age 40 years with deterioration of
central and color vision due to the 8993T>G
mitochondrial mutation. Two of her sons had
NARP syndrome. A third son was clinically
diagnosed with Leigh syndrome and died at age
4 years, prior to the recognition of the mutation
in this family. The mother's mutation load was
50% mutant mtDNA, while her sons with NARP
had 75% mutant mtDNA. The authors stated that
Leigh disease is related to 90% of heteroplasmy
(varying mixture of mutant and normal
mitochondrial DNA). This family illustrated the
remarkably variable expression of retinal and
systemic manifestations related to the 8993T>G
Santorelli FM and Tessa A. Neuropathy, ataxia and retinitis pigmentosa (NARP) syndrome. Orphanet Encyclopedia. April 2004.
http://www.orpha.net/data/patho/GB/uk-NARP.pdf
2
mutation, ranging from an isolated late-onset
cone-rod
dystrophy
to
a
severe
neurodegenerative process with a dramatic
outcome.
The clinical phenotype of NARP may worsen in
subsequent generations and usually presents as
MILS, the onset of which is in the first few
months of life. MILS patients have a rapidly
progressive
neurodegenerative
disorder
pathologically characterized by bilateral lesions
in the brainstem, basal ganglia, thalamus and
spinal cord, and clinically by psychomotor delay,
respiratory distress, and basal ganglia
dysfunction.
Diagnostic methods
Electromyography
and
nerve
conduction
velocities show findings compatible with a
sensory-motor peripheral neuropathy.
Neuroimaging is usually silent in early stages but
it may reveal signs of brainstem degeneration in
the course of the disease.
Ophthalmological examination is strongly
recommended since it may reveal a salt-andpepper retinopathy even prior to the onset of
visual field constriction, and night blindness.
Fundus examination usually shows diffuse
peripheral bone spicule formation, optic nerve
pallor, and arteriolar attenuation consistent with
retinitis pigmentosa. Electroretinogram (ERG) is
also suggested. It usually evidence markedly
decreased amplitudes and prolonged implicit
time of the photopic b wave and the flicker
response, with a significant, but relatively
smaller, decrease in amplitude and prolonged
implicit time of the scotopic b wave [Chowers et
al., 1999].
Muscle biopsy is usually unremarkable, though
neurogenic changes can be observed.
Respiratory chain enzyme studies in a biopsy of
skeletal muscle specimen might be unnecessary
because results usually fall within normal values.
Screening for alterations in the MTATP6 gene
from peripheral blood is practical in NARP
patients since identification of a point mutation
reinforces the clinical diagnosis. Mutant load
usually remains constant in different tissues at
different ages [White et al., 1999a].
Genetic counseling
NARP is maternally transmitted. Affected women
can transmit their mutation to all of their
offspring.
Prenatal diagnosis
Prenatal diagnosis for mtDNA mutations in
chorion villi or amniocytes has been hindered by
an inability to predict accurately the clinical
severity expected from a mutant load measured
in fetal tissue. After reviewing 44 published and
12 unpublished pedigrees, White et al. (1999b)
considered the possibility of prenatal diagnosis
for the common mtDNA mutations at nucleotide
8993 associated with NARP. They correlated the
severity of symptoms to the mutant load and
predicted the clinical outcome of a given mutant
load. They also used the available data to
generate empirical recurrence risks for genetic
counseling, which may be used in conjunction
with prenatal diagnosis.
Management
The therapeutic tools currently available for the
treatment of NARP, as for many mitochondrial
diseases due to mtDNA mutations, are limited
and their efficacy is not yet well established.
Coenzyme Q10 has been proposed at high
dose.
Unresolved questions
Our lack of knowledge on the pathological
mechanisms underlying NARP syndrome
reflects the present lack of efficient therapies.
Geromel et al. (2001) investigated the oxidative
stress resulting from the mutation in MTATP6
using cultured skin fibroblasts from two NARP
patients presenting with an isolated complex V
deficiency. A massive induction of the
superoxide dismutase (SOD1) activity was
observed in these fibroblasts harboring more
than 90% of mutant mitochondrial DNA. The
oxidative stress denoted by the high SOD1
activity was associated with increased cell death.
Complex
V-deficient
fibroblasts
were
successfully rescued by perfluoro-tris-phenyl
nitrone, an antioxidant spin-trap molecule. The
authors hypothesized that the superoxide
production associated with the ATPase
deficiency triggered by the NARP mutation could
be sufficient to override cell antioxidant defenses
and to result in cell commitment to die. More
recently the effectiveness of antioxidant agents
(namely, N-acetylcysteine, coenzyme Q10 and
dihydrolipoic) in cultured NARP cells suggests
that they might have a potential beneficial role in
the treatment of patients with NARP [Mattiazzi et
al., 2004]. Allotopic expression of the wild-type
MTATP6 gene and subsequent transfer to the
mitochondria may be a future application of gene
therapy [Manfredi et al., 2002].
References
Carrozzo R, Tessa A, Vazquez-Memije ME,
Piemonte F, Patrono C, Malandrini A, DionisiVici C, Vilarinho L, Villanova M, Schagger H,
Federico A, Bertini E, Santorelli FM. The
T9176G mtDNA mutation severely affects ATP
production and results in Leigh syndrome.
Neurology 56: 687-90, 2001.
Santorelli FM and Tessa A. Neuropathy, ataxia and retinitis pigmentosa (NARP) syndrome. Orphanet Encyclopedia. April 2004.
http://www.orpha.net/data/patho/GB/uk-NARP.pdf
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Chowers I, Lerman-Sagie T, Elpeleg ON, Shaag
A, Merin S. Cone and rod dysfunction in the
NARP syndrome. Br. J. Ophthalmol. 83: 190193, 1999.
Geromel V, Kadhom N, Cebalos-Picot I, Quari
O, Polidori A, Munnich A, Rotig A, Rustin P.
Superoxide-induced massive apoptosis in
cultured
skin
fibroblasts
harboring
the
neurogenic ataxia retinitis pigmentosa (NARP)
mutation in the ATPase-6 gene of the
mitochondrial DNA. Hum Molec Genet 10: 12211228, 2001.
Holt IJ, Harding AE, Petty RKH, Morgan-Hughes
JA. A new mitochondrial disease associated with
mitochondrial DNA heteroplasmy. Am J Hum
Genet 46: 428-433, 1990.
Kerrison JB, Biousse V, Newman NJ.
Retinopathy of NARP syndrome. Arch. Ophthal.
118: 298-299, 2000.
Manfredi G, Fu J, Ojaimi J, Sadlock JE, Kwong
JQ, Guy J, Schon EA. Rescue of a deficiency in
ATP synthesis by transfer of MTATP6, a
mitochondrial DNA-encoded gene, to the
nucleus. Nature Genet. 30: 394-399, 2002.
Mattiazzi M, Vijayvergiya C, Gajewski CD,
DeVivo DC, Lenaz G, Wiedmann M, Manfredi G.
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an impairment of oxidative phosphorylation that
can be improved by antioxidants. Hum Mol
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Porto FBO, Mack G, Sterboul M.-J, Lewin P,
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cone-rod dystrophy revealing a familial
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retinitis pigmentosa syndrome with the T8993G
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935-937, 2001.
Santorelli FM, Shanske S, Jain KD, Tick D,
Schon EA, DiMauro S. A T->C mutation at nt
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Thyagarajan D, Shanske S, Vazquez-Memije M,
De Vivo D, DiMauro S. A novel mitochondrial
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1995.
White SL, Shanske S, McGill JJ, Mountain H,
Geraghty MT, DiMauro S, Dahl HHM, Thorburn
DR. Mitochondrial DNA mutations at nucleotide
8993 show a lack of tissue- or age-related
variation. J. Inherit. Metab. Dis. 22: 899-914,
1999a.
White SL, Collins VR, Wolfe R, Cleary MA,
Shanske S, DiMauro S, Dahl HHM, Thorburn
DR. Genetic counseling and prenatal diagnosis
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Santorelli FM and Tessa A. Neuropathy, ataxia and retinitis pigmentosa (NARP) syndrome. Orphanet Encyclopedia. April 2004.
http://www.orpha.net/data/patho/GB/uk-NARP.pdf
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