French Canadian Patients Research Articles

Citrin deficiency, a perplexing global disorder

Citrin deficiency, caused by mutations in SLC25A13, can present with neonatal intrahepatic cholestasis or with adult onset neuropsychiatric, hepatic and pancreatic disease. Until recently, it had been thought to be found mostly in individuals of East Asian ancestry. A key diagnostic feature has been the deficient argininosuccinate synthetase (ASS) activity (E.C. 6.3.4.5) in liver, with normal activity in skin fibroblasts. In this series we describe the clinical presentation of 10 patients referred to our laboratories for sequence analysis of the SCL25A13 gene, including several patients who presented with elevated citrulline on newborn screening. In addition to sequence analysis performed on all patients, ASS enzyme activity, citrulline incorporation and Western blot analysis for ASS and citrin were performed on skin fibroblasts if available. We have found 5 unreported mutations including two apparent founder mutations in three unrelated French-Canadian patients. In marked contrast to previous cases, these patients have a markedly reduced ASS activity in skin fibroblasts. The presence of citrin protein on Western blot in three of our cases reduces the sensitivity of a screening test based on protein immunoblotting. The finding of citrin mutations in patients of Arabic, Pakistani, French Canadian and Northern European origins supports the concept that citrin deficiency is a panethnic disease.

Phenotypic variability among patients with hyperornithinaemia–hyperammonaemia–homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15

Background:Hyperornithinaemia–hyperammonaemia–homocitrullinuria (HHH) syndrome (OMIM 238970) is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15. To date, 22 different mutations of the SLC25A15 gene...

Fear of Cancer Recurrence Inventory: development and initial validation of a multidimensional measure of fear of cancer recurrence

Despite the fact that the fear of cancer recurrence is to varying degrees almost universal in cancer survivors, there is a lack of validated multidimensional instruments to evaluate this issue specifically. The goal of this study was to develop and empirically validate a multidimensional self-report scale for assessing the fear of cancer recurrence, the Fear of Cancer Recurrence Inventory (FCRI). A provincial medical databank was used to randomly select a pool of 1,704 French-Canadian patients who had been treated for breast, prostate, lung, and colorectal cancer within the past 10 years. Of these, 300 patients were asked to complete the FCRI on two occasions. The factorial analysis conducted on the final 42-item scale revealed a seven-component solution (64% of the variance) including the following factors: triggers, severity, psychological distress, coping strategies, functioning impairments, insight, and reassurance. The results also supported the internal consistency (alpha = 0.95) and the temporal stability (r = 0.89) of the FCRI, as well as its construct validity with other self-report scales assessing fear of cancer recurrence (r = 0.68 to 0.77) or related constructs such as psychological distress (r = 0.43 to 0.77) and quality of life (r = -0.20 to -0.36). This study suggests that the French-Canadian version of the FCRI is a reliable and valid instrument for evaluating the multidimensional aspects of the fear of cancer recurrence.

G.P.10.15 Genotype–phenotype correlation and identification of new mutations in non-dystrophic myotonias

Background: Non-dystrophic myotonias are rare disorders involving chloride (CLCN1) or sodium (SCN4A) channels. Affected individuals often present with similar complaints of muscle stiffness and weakness. Specific clinical signs in combination with electrophysiologic testing may help distinguish between a chloride and a sodium channel mutation. Objectives: To establish genotype/phenotype correlations in a large cohort of French-Canadian patients with non-dystrophic myotonias. Methods: We evaluated 38 subjects (from 25 families) with non-dystrophic myotonia, which is amongst the largest cohorts described so far.

Ataxia-oculomotor apraxia 2 patients show no increased sensitivity to ionizing radiation

Mutations in senataxin have been described recently in 24 cases of French-Canadian descent with ataxia-oculomotor apraxia 2. This recessive ataxia is associated with an elevation in alpha-fetoprotein as in ataxia-telangiectasia. Because ataxia-telangiectasia cells are highly radiosensitive, we used a colony survival assay to measure the radiosensitivity of lymphoblastoid cell lines derived from five French-Canadian patients with ataxia-oculomotor apraxia 2. Two were homozygous for the common French-Canadian L1976R SETX missense mutation; the three others were compound heterozygotes for the common mutation and three different missense mutations. Overall, lymphoblastoid cell lines derived from these cases did not show significant variation from a normal response to 1 Gray of ionizing radiation but the two patients who were homozygous for the common L1976R mutation fell in the intermediate or non-diagnostic range.

Higher Frequency of Familial Clustering of Prostate Cancer in French-Canadian Men

Prostate cancer is the second cause of cancer related death in North American men. We investigated the frequency of familial clustering in a French-Canadian population of prostate cancer cases. Between October 2004 and September 2005, 179 consecutively seen patients with localized prostate cancer identified each of their parents as being of French-Canadian descent. They were asked for their family history of cancer in first-degree relatives, age at diagnosis, whether affected relatives were alive, age and markers of tumor aggressiveness, including prostate specific antigen, Gleason and disease stage. ANOVA was used to compare the distribution of quantitative factors according to qualitative factors identified in our population. Differences between qualitative factors were assessed by the Fisher exact test. All p values were 2-sided. Mean age at diagnosis was 67 years. A total of 45 French-Canadian patients (25.1%) had at least 1 first-degree relative with prostate cancer, including 34 (19%) with 1 first-degree relative, 9 with a father-son pair, 25 with a brother-brother pair and 11 (6.1%) with at least 2 first-degree relatives. In our series the frequency of familial clustering defined by at least 1 relative with prostate cancer was high. We found a higher percent of French-Canadian men with at least 1 first-degree relative with prostate cancer than what was previously reported for an unselected population in Canada (25.1% vs 14.7%, p <0.0001). Those preliminary results open a new perspective to a better understanding of familial prostate cancer in the Province of Quebec.

LRRK2 is not a Significant Cause of Parkinson's Disease in French-Canadians

An old founder mutation (G2019S) was found with high frequency in the North African Arabs (30%) and Ashkenazi Jews (18% ). Demonstrate if mutations in the LRRK2 gene are a significant cause of Parkinson's disease (PD) in the French-Canadian founder population. Cases were recruited through a designated movement disorder clinic in Quebec City. Every index case had to meet the Ward and Gibb criteria for PD. Controls consisted of a non-disease group of similar age and ethnicity as the cases. Exons 31 and 41 of LRRK2 were amplified by PCR with intronic primers in all 125 PD cases and directly sequenced on an ABI 3700 sequencer. Six single nucleotide polymorphism were typed in 125 PD cases and 95 normal controls. Associations between unrelated cases and matched controls were analyzed. Single marker analysis and haplotype association tests were performed. Sequencing analysis did not reveal any reported or novel mutations in exons 31 and 41 of LRRK2. The G2019S mutation as well as mutations affecting amino acid 1441 were absent in the 125 patients. The case-control association study performed to detect the presence of a common variant in LRRK2 did not provide any positive signal. Single-marker and haplotype analyses systematically gave non-significant P values. We performed a case-control association study in 125 French-Canadian (FC) patients with PD and 95 FC controls and found that common variants in LRRK2 are unlikely to be a significant cause of late-onset PD in this founder population.

Lipid abnormalities in young patients with attention‐deficit/hyperactivity disorder

Abnormal levels of long-chain polyunsaturated fatty acids (PUFA), particularly omega-3 fatty acid (FA), have been associated with a variety of behavioural deviations, including attention-deficit/hyperactivity disorder (ADHD). The aims of our study were to define the lipid status and fatty acid composition in 37 young French-Canadian patients with ADHD (6–12 years) matched by sex and age with 35 healthy controls. Consistent differences were noted in plasma lipids (triglycerides, total cholesterol, and phospholipids), lipoproteins (LDL-cholesterol, HDL-cholesterol) and apolipoproteins (Apo A-I, Apo B-100) of the subjects with ADHD. Furthermore, the proportion of omega-3 FA was significantly altered as well illustrated by the decrease in alpha-linolenic acid (ALA, p≤0.004) and the increase in EPA and DHA (p≤0.04). On the other hand, a raise of palmitic acid (p≤0.03) and a decline in oleic acid (p≤0.0001) were detected. These changes led to abnormally low ratios of PUFA/Saturates (p≤0.02), ALA/EPA (p≤0.002) and ALA/LA (p≤0.01), concomitant with a high ratio of DHA/AA (p≤0.04). Overall, this clinical survey was able to provide us with an insight into the association of ADHD with especially abnormal FA composition. Studies are underway to delineate the mechanisms.

Deafblindness in French Canadians from Quebec: a predominant founder mutation in the USH1Cgene provides the first genetic link with the Acadian population

Genetic characterisation of 15 French Canadian patients from different regions of the province of Quebec who were clinically diagnosed as USH1 reveals that carriers of the c.216G>A-allele haplotype belong to the early founders of both the Acadian and the Quebec population.

Action myoclonus–renal failure syndrome: A cause for worsening tremor in young adults

Action myoclonus–renal failure syndrome (AMRF) is an autosomal recessive disorder first described in 4 French Canadian patients, followed by a recent description of 15 cases from various countries.1,2 The condition independently affects the kidney, with focal glomerulosclerosis causing renal failure and the brain causing progressive myoclonus epilepsy (PME) or progressive myoclonic ataxia (PMA).3,4 Tremor is often an early feature. The diagnosis of tremor and myoclonus in patients with severe renal disease is challenging. Here we highlight the evolution of tremor in this syndrome in two new cases and emphasize problems in early diagnosis. ### Case 1. Case 1 is an Australian man of English ancestry with unrelated parents (figure). He was well until age 20 when end-stage renal failure developed, after a 3-month history of anorexia, nausea, and lethargy. Renal ultrasound demonstrated small kidneys; the etiology of renal failure was not established and renal biopsy not performed. He was treated with dialysis. Figure. Pedigrees of the two subjects (filled symbols) with action …

A novel autosomal recessive limb-girdle muscular dystrophy with quadriceps atrophy maps to 11p13-p12

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of pathologies. We have identified a cohort of 14 French-Canadian patients from eight different families displaying a novel form of LGMD with an autosomal recessive inheritance. These patients share some features with previously described cases of 'quadriceps myopathy' that evolved into an LGMD. All demonstrate quadriceps femoris asymmetrical atrophy. Creatine kinase values were variable from normal to 6000 U/l. Clinical evaluations and MRI studies demonstrate a variable intrafamilial and interfamilial phenotype. Asymmetrical muscle involvement was clinically observed and confirmed by imaging. MRI studies suggest that the hamstrings and the adductor magnus are the first limb muscles to demonstrate fatty infiltration. Muscle pathology shows no sign of active inflammation but increased endomysial connective tissue associated with basal lamina duplication and collagen disorganization. A genome-wide scan using the two largest families uncovered linkage to marker D11S1360 on chromosome 11p12 [multipoint logarithm of the odds (LOD) score of 2.78]. Further genotyping for the eight families confirmed linkage to this new LGMD locus (multipoint LOD score of 4.56). Fine mapping subsequently defined a less than 3.3 cM candidate interval on 11p13-p12. Haplotype analysis of carrier chromosomes suggests that the most frequent mutation may account for up to 81.3% of French-Canadian mutations. In this study, we describe the chromosomal locus of a new form of recessive LGMD with prominent quadriceps femoris atrophy.

Combined methylmalonic aciduria and homocystinuria ( cblC): Phenotype–genotype correlations and ethnic-specific observations

Methylmalonic aciduria and homocystinuria, cblC type (MIM 277400), is the most frequent inborn error of vitamin B 12 (cobalamin, Cbl) metabolism, caused by an inability of the cell to convert Cbl to both of its active forms (MeCbl, AdoCbl). Although considered a disease of infancy, some patients develop symptoms in childhood, adolescence, or adulthood. The gene responsible for cblC, MMACHC, was recently identified. We studied phenotype–genotype correlations in 37 patients from published case-reports, representing most of the landmark descriptions of this disease. 25/37 had early-onset disease, presenting in the first 6 months of life: 17/25 were found to be either homozygous for the c.271dupA mutation ( n = 9) or for the c.331C > T mutation ( n = 3), or compound heterozygotes for these 2 mutations ( n = 5). 9/12 late-onset cases presented with acute neurological symptoms: 4/9 were homozygous for the c.394C > T mutation, 2/9 were compound heterozygotes for the c.271dupA and c.394C > T mutations, and 3/9, for the c.271dupA mutation and a missense mutation. Several observations on ethnic origins were noted: the c.331C > T mutation is seen in Cajun and French-Canadian patients and the c.394C > T mutation is common in the Asiatic-Indian/Pakistani/Middle Eastern populations. The recognition of phenotype–genotype correlations and the association of mutations with specific ethnicities will be useful for identification of disease-causing mutations in cblC patients, for carrier detection and prenatal diagnosis in families where mutations are known, and in setting up initial screening programs in molecular diagnostic laboratories. Further study into disease mechanism of specific mutations will help to understand phenotypic presentations and the overall pathogenesis in cblC patients.

Functional mutations of the ABCA1 gene in subjects of French–Canadian descent with HDL deficiency

Mutations in the ABCA1 gene cause defective cellular lipid efflux and severe familial HDL deficiency. We examined the prevalence of mutations at the ABCA1 gene in 58 unrelated probands of French–Canadian descent with HDL deficiency (HDL-C < 5th percentile). A defective cellular cholesterol or phospholipid efflux (<75% and <70% of normal controls, respectively) was identified in 14/58 (24%) of subjects. Using direct sequencing of the ABCA1 gene, we found mutations in 12/58 (∼20%) of subjects. Four probands were previously identified with diverse ABCA1 gene defects. However, we identified a novel frameshift mutation (F1840L, L1869X); a proband was heteroallelic for the N1800H mutation, previously reported in a case of Tangier disease, and a novel missense mutation (Q2210H); a novel variant (G616V), predicted to impart a functional defect in the protein, was also found in another proband. Three probands had the S1731C mutation, while two others had the R1851X and K776N documented mutations, respectively. Taken together, these data suggest that ∼20% of French–Canadian patients with severe HDL deficiency are associated with a defective ABCA1. Interestingly, in two families studied, mutations in the ABCA1 gene did not segregate with the lipid efflux defect, suggesting that other proteins are involved in the ABCA1-mediated cellular lipid efflux.

Novel Classification of Idiopathic Inflammatory Myopathies Based on Overlap Syndrome Features and Autoantibodies

Our objective was to improve the currently imperfect classifications of idiopathic inflammatory myopathies (IIM). In clinical practice, overlap features are common in IIM. This provided a rationale for positioning overlap clinical features at the core of a new classification system. We conducted a longitudinal study of 100 consecutive adult French Canadian patients with IIM. Clinical and laboratory data were obtained by retrospective chart review. Sera were analyzed for autoantibodies (aAbs) by protein A-assisted immunoprecipitation and double immunodiffusion. Overlap aAbs encompassed aAbs to synthetases, systemic sclerosis-associated aAbs, anti-signal recognition particle (SRP) and anti-nucleoporins. Patients were classified both at IIM diagnosis, based on data at presentation, and at the end of follow-up, based on cumulative findings. Three classifications were used: 1) the Bohan and Peter original classification, 2) a new version of that classification as modified by us, and 3) a novel clinicoserologic classification. As investigators were blinded to aAb results, the modified classification is strictly a clinical classification. Its core concept is the attribution of diagnostic significance to the presence of overlap features, that is, their presence resulted in a diagnosis of overlap myositis (OM). This approach allowed direct comparison with the original Bohan and Peter classification. By integrating aAb results to the modified classification, we also defined the clinicoserologic classification, which allowed to examine the added value of aAbs to diagnostic, therapeutic and prognostic stratification. Whereas polymyositis (PM) was the most common IIM according to the original classification, accounting for 45% of the cohort at diagnosis, its frequency fell to 14% with the modified classification. Conversely, while the frequency of myositis associated with connective tissue disease was 24% according to the original classification, the frequency of OM was 60% when using the modified classification. At last follow-up, the frequency of PM fell further to only 9%, while the frequency of OM rose to 67%. Systemic sclerosis was the most common connective tissue disease associated with IIM, accounting for 42.6% of OM patients and 29% of the cohort. The frequencies of overlap aAbs in the cohort and in OM patients were 48% and 70.5% (n =48/68), respectively. The presence of overlap aAbs at IIM diagnosis identified additional OM patients unrecognized by the modified classification. The sensitivity of the modified classification for OM at diagnosis was 87%, suggesting that clinicians may rely on the modified classification for identification of most OM patients, while awaiting results of aAb assays. The new classifications predicted the response to prednisone and IIM course. Using stringent definitions, IIM was classified as responsive or refractory after an adequate initial corticosteroid therapy, and the disease course as monophasic or chronic after a single adequate trial of prednisone. PM was always chronic and was associated with the highest rate (50%) of refractoriness to initial corticosteroid treatment. Dermatomyositis was almost always chronic (92% rate); however, its responsiveness to initial corticosteroid treatment was high (87%). OM was almost always responsive to corticosteroids (89%-100% rates). When OM patients were divided according to aAb subsets, anti-synthetase, SRP, or nucleoporin aAbs were markers for chronic myositis, whereas aAbs to U1RNP, Pm-Scl, or Ku were markers for monophasic myositis. We conclude that the original Bohan and Peter classification should be abandoned as it leads to misclassification of patients. Much of IIM is composed of OM. The proposed modified and clinicoserologic classifications have diagnostic, prognostic, and therapeutic value.

Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians

Hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM 201300) is a rare recessive neuropathy typically diagnosed in the first decade. The 1973 study of a French Canadian family led to the definition of HSAN2. To demonstrate that the apparent higher prevalence of HSAN2 in Quebec is due to the presence of two HSN2 mutations and that carriers of different mutations appear to have a similar phenotype. Through attending physicians, the authors recruited French Canadian patients with HSAN2. Exclusion of linkage to the known HSAN loci and linkage to the HSAN2 was performed using standard methods. Sequencing of the HSN2 gene was used to uncover the causal mutations. A large cluster of HSAN2 patients comprising 16 affected individuals belonging to 13 families was identified. The mode of inheritance is clearly autosomal recessive. All patients originated from southern Quebec, and 75% are from the Lanaudière region. Whereas linkage to the HSAN1, 3, and 4 loci was excluded, linkage to the 12p13.33 HSAN2 locus was confirmed. Sequencing of the HSN2 gene uncovered two French Canadian mutations and a novel nonsense mutation in a patient of Lebanese origin, all predicted to lead to truncations of the HSN2 protein. The comparison of clinical variables between patients with different genotypes does not suggest any difference in phenotype. Two founder mutations are responsible for the apparently higher prevalence of HSAN2 in French Canadians. Genotype-phenotype correlation does not suggest any significant clinical variability.

Neurofilament M gene in a French-Canadian Population with Parkinson’s Disease

Recently, a single base pair substitution (G1747A) mutation of the neurofilament M (NF-M) gene was reported in a French-Canadian patient with early onset Parkinson's disease (PD). Three unaffected siblings were found to be heterozygotes for the NF-M Gly336Ser mutation but, to date, no other affected PD individuals have been found with a similar mutation. No other individuals with Parkinson's disease and of similar ethnic background have been screened for this mutation. We screened 102 French-Canadian patients with definite PD and 45 French-Canadian controls for this substitution in the NF-M gene using a PCR-restriction enzyme digestion method. None of the patients or controls carried this mutation. Our results would indicate that this mutation is not common even in a PD population of similar ethnic background and suggest this change represents a rare variant. However, these results do not exclude the possibility that other mutations in this gene could be present.

Action myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder.

Action myoclonus-renal failure syndrome (AMRF) is a distinctive form of progressive myoclonus epilepsy associated with renal dysfunction. The syndrome was not recognized prior to the advent of dialysis and renal transplantation because of its rapidly fatal course if renal failure is untreated. The first and only description of AMRF was in four French Canadian patients in three families (Andermann et al., 1986). We now describe 15 individuals with AMRF from five countries, including a follow-up of the four French Canadian patients, allowing a more complete characterization of this disease. Our 15 patients with AMRF belong to nine different families. Segregation analyses were compatible with autosomal recessive inheritance. In addition, our findings show that AMRF can present with either renal or neurological features. Tremor (onset 17-26 years, mean 19.8 years, median 19 years) and progressively disabling action myoclonus (onset 14-29 years, mean 21.7 years, median 21 years), with infrequent generalized seizures (onset 20-28 years, mean 22.7 years, median 22 years) and cerebellar features are characteristic. Proteinuria, detected between ages 9 and 30 years in all cases, progressed to renal failure in 12 out of 15 patients within 0-8 years after proteinuria detection. Brain autopsy in two patients revealed extraneuronal pigment accumulation. Renal biopsies showed collapsing glomerulopathy, a severe variant of focal glomerulosclerosis. This study extends the AMRF phenotype, and demonstrates a more extensive ethnic and geographic distribution of a syndrome originally believed to be confined to individuals of French Canadian ancestry. The independent progression of neurological and renal disorders in AMRF suggests a unitary molecular lesion with pleiotropic effects. Our results demonstrate that the renal lesion in AMRF is a recessive form of collapsing glomerulopathy. Genes identified for focal segmental glomerulosclerosis and involved with the function of the glomerular basement membrane and related proteins are thus good candidates. Treatment can improve quality of life and extend the lifespan of these patients. Dialysis and renal transplantation are effective for the renal but not the neurological features, which continue to progress even in the presence of normalized renal function; the latter can be managed with anti-myoclonic and anti-epileptic drugs.

Action myoclonus-renal failure syndrome: the definitive clinico-pathological description

The causes of myoclonus are protean and often obscure; none more obscure than the action myoclonus–renal failure (AMRF) syndrome reported in four French Canadian patients from the province of Quebec by Andermann et al . in 1986. In their current paper, Andermann and colleagues transform this condition from a local rarity to one of global significance, identified in families from Canada, the USA, Cuba, Europe and Australia (Badhwar et al ., 2004). Patients in their series presented in the second and third decades of life with renal, neurological or combined features. Tremor was usually followed by the development of progressively disabling myoclonus on voluntary movement, coupled with cerebellar signs, infrequent generalized seizures, but preserved cognitive function. Renal disease presented as proteinuria and progressed to renal failure. Renal biopsy revealed collapsing glomerulopathy, a severe variant of focal segmental glomerulosclerosis that is more commonly seen in the setting of human immunodeficiency virus infection. …

Association between 7q31 markers and Tourette syndrome.

Tourette syndrome (TS) is a complex neuropychiatric disorder with a strong genetic basis. Although no specific susceptibility genes have been identified for TS, cytogenetic studies in selected cases suggest the existence of a predisposing gene located in the 7q31 chromosomal region. In order to test the hypothesis of a possible relationship between this region and TS at the population level, we undertook a family based association study in a sample of French Canadian patients from Quebec. For this purpose, markers D7S522, D7S523, and D7S1516 were tested using the extended transmission disequilibrium test (e-TDT). Marker D7S522 showed a biased transmission of alleles from heterozygote parents to their TS offsprings (allele-wise TDT chi(2) = 12.61, 4 df, P = 0.013, genotype-wise TDT chi(2) = 15.49, 7 df, P = 0.030). When the analysis was restricted to patients without ADHD or OCD comorbidity, similar results were observed both allele and genotype-wise (chi(2) = 10.68, 4 df, P = 0.03 and chi(2) = 12.55, 5 df, P = 0.028, respectively). In addition, marker D7S523 was also associated (allele-wise TDT chi(2) = 18.37, 7 df, P = 0.01 and genotype-wise TDT chi(2) = 46.26, 17 df, P = 0.00016), and showed a tendency for association in the comorbidity-free subgroup (genotype-wise TDT chi(2) = 18.7, 10 df, P = 0.044). Finally, marker D7S1516, contained in the inner mitochondrial membrane peptidase 2 like (IMMP2L) gene, also showed a tendency for association (genotype-wise TDT chi(2) = 32.87, 21 df, P = 0.048). These results may reflect the proximity of markers D7S522, D7S523, and possibly D7S1516 to a gene or regulatory region relevant to TS predisposition.

Frequent mutation reversion inversely correlates with clinical severity in a genetic liver disease, hereditary tyrosinemia

Hereditary tyrosinemia type I (HTI), a severe disease affecting primarily the liver, is caused by a deficiency of fumarylacetoacetate hydrolase (FAH). HTI is clinically heterogeneous, with no correlation between genotype and phenotype. Reversion of FAH mutant alleles in livers of HTI patients was reported previously, but the clinical significance of this phenomenon has not been fully documented. In the present study, the mosaic expression of FAH was analyzed by immune cytochemistry in liver specimens from a cohort of 26 French-Canadian HTI patients who underwent liver transplantation and related to the histopathologic status of the liver and the clinical history. Reversion was observed in 88% of patients with reverted surfaces ranging from 0.1% to 85%. Patients with the chronic form had a much higher surface of reversion (average, 36%) than those with the acute form (average, 1.6%) and a lower incidence of liver dysplasia. Within reverted nodules, hepatocytes had a normal appearance and showed no dysplasia. Hepatocellular carcinoma was observed only in FAH-negative regions. In summary, the extent of mutation reversion of the FAH gene in the liver of HTI patients was inversely correlated with the clinical severity of the disease, suggesting that the corrected hepatocytes play a substantial protective role in liver function.