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Cerebellar Vermis Defect, Oligophrenia, Congenital Ataxia, and Hepatic Fibrocirrhosis without Coloboma and Renal Abnormalities: Report of Three Cases
Abstract
We describe 3 children (2 siblings aged 10 and 3 years, and 1 sporadic case aged 13 years) with cerebellar vermis defect associated with oligophrenia, congenital ataxia, and hepatic fibrocirrhosis. Differently from what is reported in COACH syndrome, coloboma and renal involvement were absent. Since in one patient hepatic involvement was subclinical and early therapy seemed to prevent disease progression, the presence of liver disease should be carefully investigated in any patient with ataxia and midline cerebellar defects.
... Other features first described as part of the COACH phenotype, such as chorioretinal coloboma and nephronophthisis (NPH), are only inconstantly found in association with CHF, while can be variably detected in other JSRDs lacking liver involvement (Gleeson et al., 2004). A variant of COACH syndrome with only JS and CHF, reported in a few patients (Gentile et al., 1996;Coppola et al., 2002), was also termed "Gentile syndrome". Phenotypic manifestations of CHF may vary from a clinically asymptomatic raise of liver enzymes and/or early-onset hepatosplenomegaly to more severe manifestations including portal hypertension, esophageal varices and liver cirrhosis. ...
... Clinical features of MKS3-mutated patients are presented in Table 2. Neuroradiological imaging of six mutated probands are presented in Figure 3, while brain MRI of COR20 and CT scan of MTI124 families have been published before (Coppola et al., 2002;Verloes and Lambotte, 1989). Three patients (25%) present a more severe malformation of the posterior fossa, with severe vermis hypoplasia (COR94 and 191) or vermis aplasia and global cerebellar hypoplasia (COR190) associated with subtentorial cystic dilatation of the cisterna magna communicating with the fourth ventricle. ...
The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the “molar tooth sign”, a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs. © 2008 Wiley-Liss, Inc.
... Other features first described as part of the COACH phenotype, such as chorioretinal coloboma and nephronophthisis (NPH), are only inconstantly found in association with CHF, while can be variably detected in other JSRDs lacking liver involvement (Gleeson et al., 2004). A variant of COACH syndrome with only JS and CHF, reported in a few patients (Gentile et al., 1996; Coppola et al., 2002), was also termed " Gentile syndrome " . Phenotypic manifestations of CHF may vary from a clinically asymptomatic raise of liver enzymes and/or early-onset hepatosplenomegaly to more severe manifestations including portal hypertension, esophageal varices and liver cirrhosis. ...
... Clinical features of MKS3-mutated patients are presented inTable 2. Neuroradiological imaging of six mutated probands are presented inFigure 3, while brain MRI of COR20 and CT scan of MTI124 families have been published before (Coppola et al., 2002;Verloes and Lambotte, 1989). Three patients (25%) present a more severe malformation of the posterior fossa, with severe vermis hypoplasia (COR94 and 191) or vermis aplasia and global cerebellar hypoplasia (COR190) associated with subtentorial cystic dilatation of the cisterna magna communicating with the fourth ventricle. ...
The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the "molar tooth sign", a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs.
... The cause of an incidental and persistent finding of fatty liver and/or cryptogenic isolated mild hypertransaminasemia (HTS) in a child may therefore tend to be more and more undervalued and wrongly included within the spectrum of "non alcoholic fatty liver disease" (NAFLD) [1]. Differential diagnosis with other more rare, and sometimes poorly known metabolic/genetic, conditions23456 in fact is imperative to avoid these patients not to profit of specific, possibly lifesaving, treatments [7] . An exceedingly high index of suspicion is therefore required, also because multiple causes sharing identical pathological findings exist [8]. ...
We report a case with the association of well self-compensated hereditary fructose intolerance and still poorly symptomatic Duchenne type muscular dystrophy. This case illustrates the problems of a correct diagnosis in sub-clinical patients presenting with "cryptogenic" hypertransaminasemia.
This chapter provides dedicated discussion on the intracranial disorders of neuro-ophthalmologic consequence in children. An integrated approach to these diseases has emerged from the proliferation of multidisciplinary clinics and programs combining expertise in pediatric neurology, neurosurgery, neuropathology, neuroradiology, neuro-oncology, and neuro-ophthalmology. The molecular and genetic aberrations involved in the pathogenesis of many of these disorders have only recently been elucidated. Refinement in neurosurgical management continues to advance the treatment of these disorders, while preventative and therapeutic measures will arise from molecular genetic research. Advances in neuroimaging have revolutionized the diagnosis of intracranial disease in children, while recent documentation of increased cancer risk in children exposed to multiple computed tomographic (CT) scans has emphasized the need to order diagnostic magnetic resonance (MR) imaging when neuroimaging is warranted [167].
EMBRYOLOGY OF EXTRA- AND INTRAHEPATIC BILE DUCTS, DUCTAL PLATE, AND DUCTAL PLATE MALFORMATION Development of Extrahepatic Bile Ducts In the human embryo, the first anlage of the bile ducts and the liver is the hepatic diverticulum or liver bud. It starts as a thickening of the endoblastic epithelium in the ventral wall of the cephalad portion of the foregut (the future duodenum), near the origin of the yolk sac; this area is termed the anterior intestinal portal. This occurs around the 7-somite (2.5-mm) stage on the 18th day. In the 19-somite (3-mm, 22nd-day) embryo the diverticulum is formed. In the 22-somite embryo, the hepatic diverticulum is a well-defined hollow structure. From the ventral and lateral surfaces of the diverticulum, on which the endoderm is in contact with the bulk of the mesoderm of the septum transversum (between the pericardial and peritoneal cavities), short sprouts of endodermal cells extend into the septum transversum to form the earliest anlage of the liver [1]. In the embryo about 5 mm in length, the diverticulum also shows a protruding bud in its distal part. Some investigators accordingly distinguish in the hepatic diverticulum a cranial part (pars hepatica) and a caudal part (pars cystica) [2]. The caudal bud or pars cystica grows in length and represents the anlage of the gallbladder, the cystic duct, and common bile duct (ductus choledochus). For up to 8 weeks of gestation, the extrahepatic biliary tree further develops through lengthening of the caudal part of the hepatic diverticulum.
Abnormalities in primary cilia lead to diseases called ciliopathies. Multiple organ involvement is the norm since primary cilia are present in most cells. When cholangiocyte cilia are abnormal, ductal plate malformation ensues leading to such conditions as congenital hepatic fibrosis, Caroli disease or syndrome, or other fibrocystic disease.
Advances in genetics and neuroimaging have revolutionized the diagnosis of intracranial disease in children. An integrated
approach to these diseases has also emerged from the proliferation of multidisciplinary clinics and programs combining expertise
in pediatric neurology, neurosurgery, neuropathology, neuroradiology, neuro-oncology, and neuro-ophthalmology. The role of
genetic defects is increasingly recognized in many intracranial disorders, and basic research elucidates their pathogenesis
at the molecular level. Refinement in neurosurgical management continues to advance the treatment of these disorders, while
preventative and therapeutic measures will arise from molecular genetic research.
Both Meckel (Gruber) syndrome (MKS; MIM 249000) and Joubert syndrome and related disorders (JSRD; MIM 213300) are rare, autosomal recessive genetic disorders that share congenital malformations of the posterior fossa or the hindbrain and are associated with defects in the structure and/or the function of the primary cilium. The cardinal features of Meckel syndrome include the triad of brain anomalies (usually an occipital encephalocele), cystic renal dysplasia, and hepatic ductal plate malformation, in conjunction with a variety of other more variable malformations, such as polydactyly. MKS is typically lethal in the perinatal period. The genetic defects in MKS involve at least five genes that localize to the primary cilium and/or the basal body. Joubert syndrome and related disorders are characterized by a complex hindbrain malformation identified on axial magnetic resonance imaging (MRI) known as the molar tooth sign (MTS), as well as intellectual disability, hypotonia, and often, abnormal respiratory pattern and/or abnormal eye movements. In addition, a broad spectrum of other congenital anomalies, including retinal dystrophy, ocular coloboma, oral frenulae and tongue tumors, polydactyly, cystic renal disease (including cystic dysplasia or juvenile nephronophthisis), and congenital hepatic fibrosis, have been described. In contrast to MKS, most children with this condition survive infancy to reach adulthood. At least seven genes cause JSRD, with the MKS3 gene more likely to be associated with hepatic fibrosis and the JSRD subtype known as COACH syndrome. In fact, the JSRD genes associated with liver (and other) phenotypes overlap with the MKS genes, illustrating the close association of these two disorders and their shared etiology in coding for proteins important in the function of the primary cilium.
To identify genetic causes of COACH syndrome
COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD).
In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced.
19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%).
Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L.
Defining and classifying congenital disorders of the cerebellum can be difficult and confusing. One reason is that some abnormalities called "malformations" are not truly (primary) developmental malformations. This applies to Chiari I "malformations" as well as to Chiari II "malformations." The latter results mainly from a prenatal cerebrospinal fluid (CSF) leak. Also disruptive cerebellar lesions are not uncommon, examples being the "vanishing cerebellum" in myelomeningocele, cerebellar lesions in very low birth weight prematurely born infants, unilateral cerebellar hypoplasia/aplasia, and probably some instances of cerebellar agenesis (CA). The cerebellar hypoplasias consist of a heterogeneous group of inherited and prenatally acquired conditions. The concept of pontocerebellar hypoplasias will need to be expanded beyond the two main types (PCH-1 and PCH-2), and demonstrate that a classification system of cerebellar malformations cannot be based on neuroimaging criteria only. Additional studies are expected to show that this also applies to the molar tooth sign, which was initially described in Joubert syndrome (JS). The JS is the prototype of midhindbrain malformation, but its delineation is still unsolved. JS may well be an overdiagnosed entity; many cases likely not having JS are on record. Rhombencephalosynapsis (RS) has been increasingly diagnosed with the advent of neuroimaging. No familial cases have been observed. Although many affected individuals have variable impairments, RS can be found in children with normal cognitive function. In this review, some of the cerebellar anomalies are briefly discussed.
Nonprogressive congenital ataxia is a complex group of disorders caused by a variety of etiologic factors, both environmental and genetic. Hereditary forms represent a substantial part of congenital ataxias, which are difficult to classify because of their phenotypic and genetic polymorphism. Despite the advances in molecular genetics, for most nonprogressive congenital ataxia the etiology is still unknown. This report describes three sons of nonconsanguineous healthy parents, who manifested a syndrome characterized by nonprogressive ataxia, mental retardation, pyramidal signs, ocular and ocular motor anomalies, associated with severe hypoplasia of the cerebellar vermis and hemispheres on neuroimaging. All the patients have presented psychomotor developmental delay. As differential diagnosis, a comparison is made between the clinical features of these patients and the previously reported cases of nonprogressive congenital ataxia. This report represents a further example of the phenotypic and genetic heterogeneity of the syndromes with congenital ataxia.
We describe a boy with manifestations of Joubert syndrome, Leber congenital amaurosis, and multicystic kidneys. In infants with unexplained neonatal tachypnea and late developmental delay, absence or hypoplasia of the cerebellar vermis should be sought. Joubert syndrome probably is an autosomal recessive disorder. In the subsequent pregnancy of the propositus' mother, we were able to make a prenatal diagnosis of Joubert syndrome, one of the first to be reported. © 1993 Wiley-Liss, Inc.
Although Joubert syndrome (JS) was first reported in 1969 by Joubert et al (21), the long-term outcome is not yet documented.
We report 19 children (4 pairs of siblings) from a single institution diagnosed with JS. Nine children were last seen between ages 10 and 18 years, seven between ages 1 and 4 years. Three children died before 3 years of age, showing marked breathing problems and minimal development. The 16 surviving children showed variable motor development, walking was typically achieved between 2 and 10 years, two children did not learn to walk. Cognitive development showed four with development quotient (DQ) of 30 or less and nine with DQ of 60-85, the others could not be judged confidently. Siblings did not show similar development and sex was not predicting outcome. The following oculomotor problems were seen: nystagmus in 11, ocular motor apraxia in six, isolated ptosis in two, and vertical gaze palsy in three. Additional features were retinal involvement in eight and kidney involvement in four, in one of them after normal previous ultrasound.
In conclusion development of children with JS can be split into distinct subgroups, with one group dying at a young age. Those who survive show variable motor and cognitive development and can be grouped into those with DQ of less than 30 or those with DQ between 60 and 85. Ophthalmo-logical and renal involvement may change or develop over the years and should be followed carefully.
Two sisters, ages 23 years and 6 years, respectively, were found to have congenital ataxia, bilateral coloboma, mental retardation and abnormal liver function. Magnetic resonance imaging showed cerebellar vermis hypoplasia in the younger girl and liver biopsy showed hepatic fibrosis in the older sister. This combination of findings suggested a diagnosis of COACH syndrome which is characterized by hypoplasia of cerebellar vermis, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis.COACH syndrome is a newly recognized condition. So far, five cases have been reported from three sibships. We report two additional cases from one sibship and suggest that several other cases may already exist in literature that were not recognized as having COACH syndrome. The occurrence of multiple cases in single sibships suggests autosomal recessive inheritance. In addition to previously described findings typical of COACH syndrome, the older of our patients showed progressive renal insufficiency with fibrocystic changes on renal biopsy. Renal function has not been described consistently in previous reports of COACH syndrome but has been abnormal in all cases in which it has been investigated. We suggest that renal insufficiency should be considered a common manifestation of COACH syndrome. © 1996 Wiley-Liss, Inc.
On the basis of 29 patients aged 1–48 years, the general clinical manifestations and natural course have been determined of a newly described autosomal recessive multisystem condition with carbohydrate-deficient glycoproteins, particularly affecting transferrin. The syndrome showed different presentations during different age periods. During infancy and early childhood failure to thrive, liver dysfunction, pericardial effusions, marked developmental delay and stroke-like episodes were most pronounced. In later childhood and adolescence stationary mental deficiency and ataxia, slowly progressive lower limb neuropathy and pigmentary retinal degeneration, as well as secondary skeletal deformities, were found to be the most disabling constituents. For the purpose of clinical recognition, a four-stage progression based on age is presented.
Three children are described from two sibships. They share infantile ataxia with hypo/aplastic vermis, hepatic fibrocirrhosis, slender-shaped skeleton, peculiar face, and moderate mental retardation. One of them had a kidney biopsy that showed mild interstitial fibrosis and amyloid deposit, but had no functional impairment. Another suffered moderate proximal tubular acidosis. Two children had unilateral or bilateral choroidal coloboma. This pattern of defects is consistent with a syndrome previously reported in two other sibships. The acronym COACH (Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma, Hepatic fibrocirrhosis) is suggested.
The Smith-Lemli-Opitz syndrome (SLOS) and the Meckel syndrome (MS) have been regarded as separate autosomal recessive entities. Recently, overlap of these two syndromes has been discussed. A sibship containing a probable new syndrome with features reminiscent of the SLOS and the MS is presented. The literature is reviewed with regard to the frequency of various malformations in these syndromes. Clinical manifestations and cerebellar abnormalities in these sibs are similar to those described in the Joubert syndrome (JS). These three cases may represent a new syndrome with features in common with SLOS, MS, and JS resulting from the same mutant gene, which exhibits considerable pleiotropy.
A family with congenital retinal blindness of Leber and multisystem malformations is described. The abnormalities in two siblings included blindness, polycystic kidneys, severe mental and motor retardation, hypoplasia of the cerebellum, deficient differentiation of cerebral neurons and other malformations. Death resulted at three and four years of age. Histologic examination of the retina in one of these children showed absence of rods and only a single layer of somewhat stubby but otherwise normal-appearing cones. Appraisal of anatomic abnormalities in various organs, together with the clinical findings, helped place the tentative time of developmental disturbance between five and seven months of gestation. It is probable that the congenital retinal blindness in a number of other patients described in the literature is also of developmental origin. Further accumulation of families with congenital retinal blindness, together with histologic examination of their retinas, kidneys and other organs, is needed before comprehensive classifications of this syndrome can be offered.
To the Editor.
—We read with interest the article by Weinstein et al1 on Leber's congenital amaurosis. While acknowledging that the combination of CNS abnormalities, hypotonia, and motor retardation with Leber's congenital amaurosis may not inevitably result in mental retardation, we would draw attention to the association of Joubert's syndrome with Leber's congenital amaurosis, first recognized by Tomita et al.2 Joubert's syndrome3 comprises episodic panting tachypnea and prolonged apnea in the neonate associated with jerky eye movements, agenesis of the cerebellar vermis, and brain-stem malformations. Subsequent ataxia, dysequilibrium, and mental handicap are the rule. We have seen five children with features of Joubert's syndrome and Leber's congenital amaurosis (Table).Autopsy in identical twins (cases 2 and 3) confirmed the retinal and renal pathologic features together with agenesis of the vermis and brain-stem dysgenesis. The importance of the respiratory irregularity had not been recognized at birth in any
A case of the Joubert Syndrome is reported. This syndrome, of which 11 cases have hitherto been described, is characterized by aplasia of the cerebellar vermis in addition to episodic hyperpnoea, abnormal eye movements, rhythmic protrusion of the tongue, ataxia, and mental retardation. The diagnosis was made by the clinical symptoms, computerized axial tomography of the brain, and lumbar pneumencephalography. Bilateral typical colobomata of retina and choroid were an additional anomaly, described for the first time in association with the Joubert Syndrome. The possible relationship between the ocular and cerebral anomalies is discussed.
Joubert syndrome is an autosomal recessive inherited condition characterized by agenesis or hypoplasia of the cerebellar vermis, retinal dystrophy, chorioretinal colobomata, oculomotor abnormalities, episodic hyperpnea, ataxia, and mental retardation. Congenital hepatic fibrosis has not previously been described in Joubert syndrome. We report two unrelated children with Joubert syndrome and hepatosplenomegaly. On histopathological examination, both had congenital hepatic fibrosis. Both were also found to have congenital medullary cystic disease of the kidneys. Joubert syndrome appears to be one of a spectrum of congenital malformation syndromes involving the central nervous system, eye, liver and kidneys.
Amongst 78 patients with either unilateral or bilateral (ponto-) cerebellar hypoplasia, atrophy or lesions on neuro-imaging (CT and/or MRI), 16 showed unilateral hypoplasia or lesions, 15 vermis defects, nine pontocerebellar hypoplasia, 10 non-progressive conditions with bilateral cerebellar hemisphere hypoplasia or lesions and 28 progressive cerebellar atrophy. Known genetic conditions did not occur with unilateral cerebellar involvement, whereas a high incidence of mostly autosomal recessively inherited diseases could be diagnosed in more than half of the patients with either pontocerebellar hypoplasia or progressive bilateral cerebellar atrophy. A minority of patients with vermis defects or non-progressive cerebellar hypoplasia suffered from genetic conditions. An overview of the literature is presented describing genetic and non-genetic syndromes, or metabolic disorders associated with cerebellar structural abnormalities. From these data, new proposals for improved diagnostic investigations will be presented.
There are several diseases characterized by renal cysts and neurological abnormalities. Joubert syndrome is distinguished by hypoplasia of the cerebellar vermis, hypotonia, retinal dystrophy characterized by abnormal eye movements, and impaired psychomotor development, together with abnormal respiratory pattern. We describe a boy with Joubert syndrome associated with multicystic renal dysplasia and hepatic fibrosis. We speculate that the association of malformations of the renal and nervous systems in this syndrome and others are not random. Concomitant malformations of these systems are likely based upon their common developmental and genetic features.
Joubert syndrome is an autosomal-recessive disorder characterized by cerebellar hypoplasia, hypotonia, developmental delay, abnormal respiratory patterns, and abnormal eye movements. The biochemical and genetic basis of Joubert syndrome is unknown and a specific chromosomal locus for this disorder has not been identified. Review of this disorder and related syndromes suggests that (1) hypoplasia of the cerebellar vermis in Joubert syndrome is frequently associated with a complex brain stem malformation represented as the "molar tooth sign" on magnetic resonance imaging, (2) the "molar tooth sign" could be present in association with the Dandy-Walker malformation and occipital encephalocele, (3) cerebellar hypoplasia is present in conditions related to Joubert syndrome such as Arima syndrome; Senior-Loken syndrome; cerebellar vermian hypoplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis syndrome; and juvenile nephronophthisis due to NPH1 mutations, and (4) the brainstem-vermis malformation spectrum is probably caused by at least two and probably several genetic loci. We have ascertained previously a cohort of 50 patients with a putative diagnosis of Joubert syndrome in order to evaluate the presence of associated malformations, and to initiate studies leading to the identification of genes causing Joubert and related syndromes. Among the associated malformations found in patients ascertained as having Joubert syndrome, 8% of patients had polydactyly, 4% had ocular colobomas, 2% had renal cysts, and 2% had soft-tissue tumors of the tongue. The WNT1 gene has been tested as a candidate gene for Joubert syndrome based on its expression in the developing cerebellum and an associated mutation in the swaying mouse. A search for mutations in WNT1 in a series of patients with Joubert syndrome did not detect mutations at this locus. This analysis suggested that mutations in WNT1 might not have a significant role in Joubert syndrome, and other functional candidate genes related to development of the cerebellum need to be examined. A genome-wide linkage analysis carried out in 10 Joubert syndrome pedigrees did not identify a specific chromosomal locus for this disorder. This observation, along with those from clinical studies, provides further evidence that Joubert and related syndromes are genetically heterogeneous.
This article describes the first patient with a deficiency of transaldolase (TALDO1 [E.C.2.2.1.2]). Clinically, the patient presented with liver cirrhosis and hepatosplenomegaly during early infancy. In urine and plasma, elevated concentrations of ribitol, D-arabitol, and erythritol were found. By incubating the patient's lymphoblasts and erythrocytes with ribose-5-phosphate and subsequently analyzing phosphate sugar metabolites, we discovered a deficiency of transaldolase. Sequence analysis of the transaldolase gene from this patient showed a homozygous deletion of 3 bp. This deletion results in absence of serine at position 171 of the transaldolase protein. This amino acid is invariable between species and is located in a conserved region, indicating its importance for enzyme activity. The detection of this new inborn error of pentose metabolism has implications for the diagnostic workup of liver problems of unknown etiology.