Biomedical subjects

Y Agid

Publications and source records attributed to Y Agid.

At least 199 records · Page 11Linked to original sources

PubMed1997

Is differential regulation of mitochondrial transcripts in Parkinson's disease related to apoptosis?

A cDNA library of substantia nigra pars compacta from a patient with Parkinson's disease (PD) was differentially screened with probes of normal and parkinsonian substantia nigra enriched in neuronal transcripts. Fifty-eight clones were isolated; 39 were subunits of mitochondrial respiratory complexes I and IV. Parallel screening of a cDNA library derived from normal substantia nigra confirmed differential representation of the transcripts in the substantia nigra pars compacta. In situ hybridization in postmortem brain from parkinsonian and control subjects, with representative complex I and complex IV probes, showed increased labeling, at the cellular level, of the complex I subunit ND1 in neurons of the lateral substantia nigra, where cell death is greatest in PD, but decreased labeling in the medial substantia nigra where fewer cells die. Expression of a complex IV subunit, COXI, increased, however, in both parts of the structure. Increased expression of ND1 and COXI was also observed in nerve growth factor-differentiated PC12 cells undergoing apoptosis induced by tumor necrosis factor-alpha, suggesting that the differential regulation of certain mitochondrial mRNAs may be associated with this form of cell death. This in vitro model of apoptosis is potentially relevant to the death of dopaminergic neurons in PD, because these cells express the tumor necrosis factor-alpha receptor, and neighboring microglial cells in patients synthesize the cytokine.

Aged↗

PubMed1997

Expression of Bcl-2 in adult human brain regions with special reference to neurodegenerative disorders.

The expression of the protooncogene bcl-2, an inhibitor of apoptosis in various cells, was examined in the adult human brain. Several experimental criteria were used to verify its presence; mRNA was analyzed by northern blot with parallel experiments in mouse tissues, by RNase protection, and by in situ hybridization histochemistry. Bcl-2 protein was detected by western blot analysis and immunohistochemistry. Two bcl-2 mRNA species were identified in the human brain. The pattern of distribution of bcl-2 mRNA at the cellular level showed labeling in neurons but not glia. The in situ hybridization signal was stronger in the pyramidal neurons of the cerebral cortex and in the cholinergic neurons of the nucleus basalis of Meynert than in the Purkinje neurons of the cerebellum. Both melanized and nonmelanized neurons were labeled in the substantia nigra. In the striatum, bcl-2 mRNA was detected in some but not all neurons. In the regions examined for Bcl-2 protein, the expression pattern correlated with the mRNA results. In patients with Alzheimer's and Parkinson's diseases, quantification of bcl-2 mRNA in the nucleus basalis of Meynert and substantia nigra, respectively, showed that the expression was unaltered compared with controls, raising the possibility that the expression of other components of apoptosis is modulated.

Aged↗

PubMed1997

Rescue of mesencephalic dopamine neurons by anticancer drug cytosine arabinoside.

Nanomolar concentrations of cytosine arabinoside (ara-C), a structural analogue of 2'-deoxycytidine (2'dC) used in the chemotherapy of cancer, proved to be highly effective in preventing the death of postmitotic dopaminergic neurons that occurs spontaneously by apoptosis in mesencephalic cultures. The rescued cells were totally functional and highly differentiated. The trophic/neuroprotective effects of ara-C were (1) specific for dopaminergic neurons; (2) long-lived, remaining detectable several days after withdrawal of the nucleoside analogue from the culture medium; (3) still observed when the treatment was delayed after plating; (4) abolished by an excess of 2'dC or dCTP, or by exposure to the neurotoxin 1-methyl-4-phenylpyridinium; and (5) mimicked by ara-CTP, 5-fluoro-2'-deoxyuridine, and aphidicolin. Autoradiographic studies revealed that ara-C was incorporated exclusively into astrocyte nuclei, suggesting that the dopaminotrophic activity was indirect and resulted from the antiproliferative action of the modified nucleoside on glial cells at concentrations that were not neurotoxic. No evidence was found for putative deleterious or trophic molecules secreted by proliferating or ara-C-treated astrocytes, respectively, suggesting that neuroglial contact may play a role. Our results suggest a possible mechanism underlying neurodegeneration in Parkinson's disease, where selective loss of dopaminergic neurons in the mesencephalon is accompanied by astrogliosis.

1-Methyl-4-phenylpyridinium↗

PubMed1997

Mitochondrial free radical signal in ceramide-dependent apoptosis: a putative mechanism for neuronal death in Parkinson's disease.

Activation of the apoptogenic sphingomyelin-dependent signaling pathway in neuronally differentiated PC12 cells with cell-permeant C2-ceramide resulted in a transient and short-lived emission of reactive oxygen species that was maximal 6 h after the beginning of treatment, followed immediately by nuclear translocation of the transcription factor nuclear factor kappaB. The production of reactive oxygen species was necessary for cell death to occur. The origin of the reactive oxygen species was identified as complex I of the mitochondrial electron transport chain. The mitochondria were not dysfunctional, however. They maintained normal membrane potentials and ATP synthesis until the cells began to die and the cell nuclei to condense and to fragment, approximately 12 h after the beginning of treatment. We conclude that a mitochondrial free radical signal plays a role in the sphingomyelin-dependent transduction pathway. Convergent data from postmortem brain suggest that this signaling pathway may be activated in the dopaminergic neurons that die in patients with Parkinson's disease and would provide a mechanism for oxidative stress implicating the mitochondria, both of which have long been hypothesized to play a role in the pathogenesis of this disease.

Animals↗

PubMed1997

Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases.

A clinical and electrophysiological study was performed in 119 Type 1A Charcot-Marie-Tooth disease (CMT1A) patients with proven 17p11.2 duplication. Onset of the first functional manifestations was in the first decade in 50% of cases and before the age of 20 years in 70% of cases. The predominant clinical signs were muscle weakness and wasting in the lower limbs. None of the patients was normal on clinical examination and all presented at least pes cavus or ankle jerk areflexia. Motor nerve conduction velocity (MNCV) was uniformly reduced in all nerves, and was < or = 33 m/s in the median nerve for all patients. Sensory potentials were abnormal in all cases, even where there was no clinical sensory loss. Needle electromyography recruitment was reduced in distal muscles for all patients. MNCV slowing was fully consistent with the presence of duplication even in clinically asymptomatic individuals or in children, confirming the complete electrophysiological penetrance of 17p11.2 duplication and making median nerve MNCV a reliable tool for screening affected at-risk individuals. Functional disability was mild. Ninety-six percent of patients were autonomous; 25% were asymptomatic and diagnosed by systematic family investigation especially on the basis of median nerve MNCV reduction. Early age at onset and greatly reduced median nerve MNCV were predictive of a more severe disease course; the earlier the onset the more reduced the median nerve MNCV and the higher the functional disability tended to be after an equivalent disease duration. Cross-sectional analysis of neurological deficit, functional deficit and MNCV according to disease duration showed that, regardless of age at onset, CMT1A disease with 17p11.2 duplication is a clinically progressive disorder. Neurological deficit and functional disability increased, whereas median nerve MNCV and compound muscle action potential (CMAP) amplitude did not change with disease course. Intrafamilial phenotype variation between parents and children and between siblings was studied in large families. Functional disability and neurological deficit differed widely and the highest range of median nerve MNCV within a family reached 23 m/s. Clinical and electrophysiological data were compared with those of CMT1B patients with peripheral myelin P0 protein point mutation. CMT1A patients were found to be more severely affected with more prolonged distal motor latency and more reduced CMAP amplitude, whereas MNCV did not significantly differ, indicating that peripheral myelin P0 protein point mutation is not always associated with a severe phenotype. The same genetic defect (17p11.2 duplication) results in variable expression within the phenotype, even in siblings with variations in age at onset, clinical severity and MNCV slowing. This phenotypic variation could be due to additional genetic factors related to peripheral myelin protein 22 expression as well as to other endogenous or environmental factors.

Adolescent↗

PubMed1997

Molecular and clinical correlations in spinocerebellar ataxia 2: a study of 32 families.

Spinocerebellar ataxia 2 (SCA2) is caused by the expansion of an unstable CAG repeat encoding a polyglutamine tract. One hundred and eighty four index patients with autosomal dominant cerebellar ataxia type I were screened for this mutation. We found expansion in 109 patients from 30 families of different geographical origins (15%) and in two isolated cases with no known family histories (2%). The SCA2 chromosomes contained from 34 to 57 repeats and consisted of a pure stretch of CAG, whereas all tested normal chromosomes (14-31 repeats), except one with 14 repeats, were interrupted by 1-3 repeats of CAA. As in other diseases caused by unstable mutations, a strong negative correlation was observed between the age at onset and the size of the CAG repeat (r = -0.81). The frequency of several clinical signs such as myoclonus, dystonia and myokymia increased with the number of CAG repeats whereas the frequency of others was related to disease duration. The CAG repeat was highly unstable during transmission with variations ranging from -8 to +12, and a mean increase of +2.2, but there was no significant difference according to the parental sex. This instability was confirmed by the high degree of gonadal mosaicism observed in sperm DNA of one patient.

Adolescent↗

PubMed1997

No effect of the alpha1-antichymotrypsin A allele in Alzheimer's disease.

The apolipoprotein E (ApoE)-epsilon4 allele is associated in a dose dependent manner to an increased risk for Alzheimer's disease. However, the ApoE-epsilon4 allele effect does not account for all patients with Alzheimer's disease, and the existence of other genetic risk factors has been postulated. Kamboh et al reported an association between Alzheimer's disease and the A allele of alpha1-antichymotrypsin (Aact) gene, which was not confirmed in a larger series more recently analysed. The ApoE and Aact genotypes were analysed in 314 patients with Alzheimer's disease and 173 healthy controls, confirming the dose dependent effect of the ApoE-epsilon4 allele. Nevertheless, even using odds ratios adjusted for age and sex, there was no significant effect of the Aact genotype on Alzheimer's disease or on the ApoE-epsilon4 allele associated risk for Alzheimer's disease.

Alleles↗

PubMed1997

Accuracy of the clinical diagnosis of corticobasal degeneration: a clinicopathologic study.

The accuracy of the clinical diagnosis of corticobasal degeneration (CBD) is unknown. To determine its diagnostic accuracy, we presented 105 cases with known neuropathologic diagnoses, including CBD (n = 10), progressive supranuclear palsy (PSP, n = 24), Parkinson's disease (n = 15), diffuse Lewy body disease (n = 14), multiple system atrophy (n = 16), postencephalitic parkinsonism (n = 7), Pick's disease (n = 7), Creutzfeldt-Jakob disease (n = 4), Alzheimer's disease (n = 4), vascular parkinsonism (n = 3), and Whipple's disease (n = 1), as clinical vignettes to six neurologists unaware of the autopsy findings. Reliability was measured with the kappa statistics. The neurologists' clinical diagnoses were compared with clinicopathologic diagnoses for sensitivity, specificity, and positive predictive values at first and last clinic visits. The group reliability for the diagnosis of CBD significantly improved from moderate for the first visit (mean = 34 months after onset) to substantial for the last (68 months after onset). For the first visit, mean sensitivity for CBD was low (35%), but specificity was near-perfect (99.6%). For the last visit, mean sensitivity minimally increased (48.3%), and specificity remained stable. False-negative misdiagnoses mainly occurred with PSP. False-positive diagnoses were rare. The extremely low sensitivity of the clinical diagnosis of CBD suggests that this disorder is markedly underdiagnosed. Although the validity of the clinical diagnosis might have been improved if neurologists could have examined these patients, more important is that this disorder was misdiagnosed by the primary neurologists. In our data set, the best predictors for the diagnosis of CBD included limb dystonia, ideomotor apraxia, myoclonus, and asymmetric akinetic-rigid syndrome with late onset of gait or balance disturbances.

Basal Ganglia↗

PubMed1997

Low-dose clozapine improves dyskinesias in Parkinson's disease.

The severity of parkinsonian motor disability and dyskinesias was evaluated in seven levodopa-responsive patients with Parkinson's disease after an acute challenge with the mixed dopamine agonist apomorphine, before and after low-dose clozapine (50 mg) for 18 +/- 2 days. There was a significant 59% improvement (p < 0.05) of apomorphine-induced dyskinesias without aggravation of parkinsonian motor disability following clozapine treatment. The results suggest that low-dose clozapine, already shown to improve psychotic symptoms, may help to reduce severe levodopa-induced dyskinesias in parkinsonian patients.

Aged↗

PubMed1997

What are the obstacles for an accurate clinical diagnosis of Pick's disease? A clinicopathologic study.

Several studies have evaluated the reliability and validity of the clinical diagnosis of Alzheimer's disease (AD) using well-defined neuropathologic criteria, but none has attempted to evaluate the diagnostic accuracy of Pick's disease. We determined the accuracy of the clinical diagnosis of Pick's by presenting 105 autopsy-confirmed cases of Pick's (n = 7) and related disorders (non-Pick's, n = 98) as clinical vignettes in randomized order to six neurologists who were unaware of the autopsy findings. The group of raters had moderate to fair agreement for the diagnosis of Pick's as measured by the kappa statistics. The sensitivity for the diagnosis of Pick's for the first visit (mean, 53 months after onset) and last visit (mean, 78 months after onset) was low (range, 0 to 71%), but specificity was near-perfect. Median positive predictive values at both visits were 83 to 85%. False-negative misdiagnoses mainly involved AD. False-positive diagnoses were rare and occurred with corticobasal degeneration (first visit) and with dementia with Lewy bodies (last visit). Pick's was also misdiagnosed by primary neurologists. The best clinical predictors for the early diagnosis of Pick's included "frontal" dementia, early "cortical" dementia with severe frontal lobe disturbances, absence of apraxia, and absence of gait disturbance at onset. However, the first neurologic evaluation in some of the Pick's cases took place in advanced stages of the disease. Our findings suggest that this disorder is underdiagnosed in clinical practice. Although the low sensitivity for the clinical diagnosis of Pick's is disappointing, our data suggest that when clinicians suspect Pick's, their diagnosis is almost always correct. Absence of awareness of the main features of this disorder and of specificity of the frontal lobe syndrome may partially explain the low detection of Pick's disease.

Aged↗

PubMed1997

Clinical and molecular features of spinocerebellar ataxia type 6.

The mutation involved in spinocerebellar ataxia type 6 (SCA6) is a small CAG expansion in the alpha-1A subunit of the voltage-dependent calcium channel gene. We looked for this mutation in 91 families with autosomal-dominant cerebellar ataxias and found that SCA6 is a minor locus in our series (2%) and is rare in France (1%). Furthermore, we did not detect the SCA6 mutation on 146 sporadic cases with isolated cerebellar ataxia or olivopontocerebellar atrophy. The normal and expanded alleles ranged from 4 to 15 and 22 to 28 CAG repeats, respectively, and age at onset was correlated to CAG repeat length (r = -0.87). In contrast with other SCA, the expanded allele was stable during transmission. Clinically, SCA6 patients (n = 12) presented with moderate to severe cerebellar ataxia with a lower frequency of associated signs compared with other SCA and a mean age at onset of 45 +/- 14 years (range, 24 to 67). MRI showed extensive cerebellar atrophy but not of the brainstem or cerebral cortex.

Adult↗

PubMed1997

Pallidal stimulation for Parkinson's disease. Two targets?

There has been renewed interest in functional surgery as treatment for Parkinson's disease (PD). Although pallidotomy and chronic pallidal stimulation are highly effective in suppressing levodopa-induced dyskinesia (LID), both methods also seem to be effective in reducing parkinsonian disability. However, the simultaneous improvement of LID and motor signs is hard to explain with the classic model of basal ganglia circuitry. Taking advantage of the fact that deep brain stimulation is reversible and that implanted electrodes contain four discrete stimulation sites, we investigated the effect of stimulation on different sites of the globus pallidus (GP) in five PD patients. Stimulation in the dorsal GP (upper contact) significantly improved gait, akinesia, and rigidity and could induce dyskinesia when patients were in the "off" state. In contrast, stimulation in the posteroventral GP (lower contact) significantly worsened gait and akinesia, although the reduction in rigidity remained. For patients in the "on" state, stimulation in the posteroventral GP dramatically reduced LID but, as in the "off" state, worsened gait and akinesia, thus canceling out the antiparkinsonian effect of levodopa. Our results indicate that stimulation had a striking different effect on parkinsonism and dyskinesia when applied at two different loci of the GP and that stimulation applied in the posteroventral GP produced opposite effects on rigidity and on akinesia. We conclude that parkinsonian signs and LID are a reflection of at least two different anatomofunctional systems within the GP and that this functional organization of the GP needs to be considered when determining the optimal target for surgical treatment of PD.

Adult↗

PubMed1997

Apolipoprotein E and Alzheimer disease: genotype-specific risks by age and sex.

The distribution of apolipoprotein E (APOE) genotypes as a function of age and sex has been examined in a French population of 417 Alzheimer disease (AD) patients and 1,030 control subjects. When compared to the APOE epsilon3 allele, an increased risk associated with the APOE epsilon4 allele (odds ratio [OR] [epsilon4] = 2.7 with 95% confidence interval [CI] = 2.0-3.6; P < .001) and a protective effect of the APOE epsilon2 allele (OR[epsilon2] = 0.5 with 95% CI = 0.3-0.98; P = .012) were retrieved. An effect of the epsilon4 allele dosage on susceptibility was confirmed (OR[epsilon4/epsilon4] vs. the epsilon3/epsilon3 genotype = 11.2 [95% CI = 4.0-31.6]; OR[epsilon3/epsilon4] vs. the epsilon3/epsilon3 genotype = 2.2 [95% CI = 1.5-3.5]). The frequency of the epsilon4 allele was lower in male cases than in female cases, but, since a similar difference was found in controls, this does not lead to a difference in OR between sex. ORs for the epsilon4 allele versus the epsilon3 allele, OR(epsilon4), were not equal in all age classes: OR(epsilon4) in the extreme groups with onset at < 60 years or > 79 years were significantly lower than those from the age groups 60-79 years. In epsilon3/epsilon4 individuals, sex-specific lifetime risk estimates by age 85 years (i.e., sex-specific penetrances by age 85 years) were 0.14 (95% CI 0.04-0.30) for men and 0.17 (95% CI 0.09-0.28) for women.

Age of Onset↗

PubMed1997

Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive cell loss confined mostly to dopaminergic neurons of the substantia nigra. Several factors, including oxidative stress, and decreased activity of complex I mitochondrial respiratory chain, are involved in the degenerative process. Yet, the underlying mechanisms leading to dopaminergic cell loss remain elusive. Morphological assessment for different modes of cell death: apoptosis, necrosis or autophagic degeneration, can contribute significantly to the understanding of this neuronal loss. Ultrastructural examination revealed characteristics of apoptosis and autophagic degeneration in melanized neurons of the substantia nigra in PD patients. The results suggest that even at the final stage of the disease, the dopaminergic neurons are undergoing active process of cell death.

Aged↗

PubMed1997

Apoptosis in dopaminergic neurons of the human substantia nigra during normal aging.

Morphological and biochemical alterations have been described in neurons of the aged human brain. However, the cell death process associated with neuronal senescence remains to be elucidated. Apoptosis and autophagic degeneration, two modes of programmed cell death described in embryogenesis and tissue renewal in adult, have been observed in nigral dopaminergic neurons in patients with Parkinson's disease. In the present study, we made the hypothesis that programmed cell death may be also involved in the death of nigral dopaminergic neurons occurring during aging. Cell death types were defined by morphological criteria identified at subcellular level. We thus performed an ultrastructural analysis in order to search for apoptotic and autophagic features in melanized neurons of the substantia nigra in four normal aged subjects. Morphological characteristics of apoptosis, such as contact loss with surrounding tissues, cell shrinkage and chromatin condensation, were found in 2% of the total number of melanized neurons analyzed. Although endoplasmic reticulum appeared normal, mitochrondria were markedly shrunken. Fragments of melanized neurons were found in glial cells. Autophagic degeneration or necrosis were not detected in melanized neurons. Signs of oxidative stress, such as vacuolation of mitochondria, were observed in melanized neurons devoid of apoptotic features. These findings demonstrate that apoptosis is involved in cell death of nigral dopaminergic neurons during normal aging. Since morphological abnormalities found in this study, such as marked mitochondrial shrinkage in apoptotic neurons, were not observed in patients with Parkinson's disease, the mechanisms underlying apoptosis may be different in aging and pathology.

Aged↗

PubMed1997

[Neuronal death caused by apoptosis in Parkinson disease].

The identity of the neuronal populations (dopaminergic, noradrenergic, serotoninergic, cholinergic) that die in Parkinson's disease is well established. The cause of this degeneration, and the mechanism by which it takes place is still unknown, although there is data, at least for the dopaminergic neurons, suggesting that oxidative stress might play a role. In addition, recent ultrastructural studies of dopaminergic neurons in patients with Parkinson's disease have shown that these neurons die by apoptosis, and immunocytochemical studies have shown that the cytokine TNF-alpha, observed in microglial cells in the substantia nigra of patients post-mortem, might play a role, as might the transcription factor NF-kappa B, which is translocated into the nucleus of dopaminergic neurons in patients, a sign of its activation. We have developed an in vitro model of dopaminergic cell death that accounts for these observations. In both differentiated PC12 cells and primary cultures of mesencephalic neurons, we have shown that when the sphingomyelin-dependent signaling pathway is activated, these cells die by apoptosis, preceded by the production of superoxide radicals in the mitochondria and the nuclear translocation of NF-kappa B. TNF-alpha is known to induce all three such events: apoptosis, activation of the sphingomyelin pathway, free radical production. Our results suggest that the superoxide radicals are used as signalling molecules within the sphingomyelin pathway. These observations may help to explain the origin of the evidence, in postmortem brain from parkinsonian patients, for oxidative stress, hypothesized to be an etiological factor in this disease.

Apoptosis↗

PubMed1996

Effect of the weaver mutation on the expression of dopamine membrane transporter, tyrosine hydroxylase and vesicular monoamine transporter in dopaminergic neurons of the substantia nigra and the ventral tegmental area.

The adult homozygous weaver mutant mouse (wv/wv) is characterized by a loss of dopamine (DA) neurons in the nigrostriatal pathway. Quantitative in situ hybridization of three different dopaminergic markers: dopamine membrane transporter (DAT), tyrosine hydroxylase (TH), and vesicular monoamine transporter (VMAT2) was performed on individual dopaminergic cells of the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA) in 2-month-old wv/wv mice, in order to investigate the metabolic state of remaining dopaminergic cell bodies and gain further insight into modifications observed on dopaminergic nerve terminals in the striatum and the nucleus accumbens. Cellular expression of DAT mRNA in remaining dopaminergic cells of both the SNC and the VTA was decreased in the wv/wv mice compared to the wild-type mice (+/+). In contrast, the expression of TH and VMAT2 mRNA remained unchanged in the wv/wv mice. Furthermore, in 7-day-old wv/wv mice, before the onset of cell death in the midbrain. DAT mRNA levels were reduced in dopaminergic neurons in both the SNC and VTA. In these animals, the cellular expression of TH mRNA remained unchanged. These results taken together indicate that DAT expression is one of the first targets in the ventral mesencephalon of the wv mutation, inducing a specific decrease of DA uptake in the striatum and the nucleus accumbens. The alteration of the DA membrane transporter could play a role in the progression of DA neuronal death in the wv mice.

Animals↗

PubMed1996

Clinical and genetic abnormalities in patients with Friedreich's ataxia.

BACKGROUND: Friedreich's ataxia, the most common inherited ataxia, is associated with a mutation that consists of an unstable expansion of GAA repeats in the first intron of the frataxin gene on chromosome 9, which encodes a protein of unknown function. METHODS: We studied 187 patients with autosomal recessive ataxia, determined the size of the GAA expansions, and analyzed the clinical manifestations in relation to the number of GAA repeats and the duration of disease. RESULTS: One hundred forty of the 187 patients, with ages at onset ranging from 2 to 51 years, were homozygous for a GAA expansion that had 120 to 1700 repeats of the trinucleotides. About one quarter of the patients, despite being homozygous, had atypical Friedreich's ataxia; they were older at presentation and had intact tendon reflexes. Larger GAA expansions correlated with earlier age at onset and shorter times to loss of ambulation. The size of the GAA expansions (and particularly that of the smaller of each pair) was associated with the frequency of cardiomyopathy and loss of reflexes in the upper limbs. The GAA repeats were unstable during transmission. CONCLUSIONS: The clinical spectrum of Friedreich's ataxia is broader than previously recognized, and the direct molecular test for the GAA expansion on chromosome 9 is useful for diagnosis, determination of prognosis, and genetic counseling.

Adolescent↗