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Technical Briefs |
1
Lab. of Clin. Chem. and Depts. of
2
Pediatrics,
3
Pathol., and
4
Med. Genetics, University Hosp., B-9000 Gent, Belgium, and
5
Dept. of Pediatrics, ASZ, B-9300 Aalst, Belgium;
a address
for correspondence: Central Lab., 1B2, University Hosp. Gent, De Pintelaan 185, B-9000 Gent, Belgium, fax ##32/9/240.49.85, e-mail joris.delanghe{at}rug.ac.be
Oral–facial–digital syndrome II (Mohr syndrome) is an autosomal recessive syndrome characterized by bilateral polysyndactylia of the halluces, bilateral hexadactylia of the hands, lobed tongue, and multiple oral frenula and peculiar facies (1). Hitherto, no biochemical abnormalities have been associated with this syndrome.
The propositus is a Caucasian boy (mixed Flemish/German descent) born
from an incestuous father–daughter relation. During the pregnancy, a
marked intrauterine growth retardation was observed. At delivery, after
a pregnancy of 40 weeks, the infant's height (35.0 cm), weight (2400
g), and head circumference (28.2 cm) were all below the first
percentile. Diagnosis of Mohr syndrome was confirmed by the observation
of polydactylia of the feet; syndactylia of toes 1–2 and 3–4 of both
feet; bifid tongue tip with broad, short uvula; bilateral hexadactylia
of the hands; and a peculiar facies with micrognathia and microcephaly.
Furthermore, the vertebral body T11 was bifurcated and transfontanellar
ultrasonography of the brain revealed slightly dilated lateral and
third ventricles. Shortly after birth, transient tachypnea and feeding
difficulties were present, which gradually disappeared. At the age of 6
weeks, a persistent jaundice was noticed: serum total bilirubin 166
µmol/L (reference interval 1–19 µmol/L) and conjugated bilirubin
115 µmol/L (reference interval 0–14 µmol/L). Stools did not
contain bile pigments. Aspartate aminotransferase (AST) (240 U/L,
reference interval 16–58 U/L), alkaline phosphatase (399 U/L,
reference interval 225–370 U/L), and 
-glutamyltransferase (782 U/L,
reference interval 11–49 U/L) were increased.
L-Alanine aminotransferase (ALT, EC 2.6.1.2) activity
(<1 U/L, reference interval 9–51 U/L) remained undetectable even
after in vitro addition of pyridoxal-5'-phosphate (P-5'-P) to exclude
ALT cofactor deficiency. Total protein (60 g/L) and albumin
concentrations (41 g/L) were normal. Serum creatinine was 36 µmol/L
(reference interval 27–53 µmol/L). Inflammatory variables C-reactive
protein (14.1 mg/L, reference interval <5 mg/L) and leukocyte count
(20.7 x 109/L, reference interval 7.0–15.3 x
109/L) were increased. All test results for infectious
etiologies were normal. Serological investigations (antibodies against
Toxoplasma gondii, Epstein Barr virus, rubella virus,
cytomegalovirus, herpes simplex virus, Treponema pallidum,
hepatitis B and C viruses, enterovirus, Coxsackie virus) were negative.
On ultrasonography the liver was homogeneously dense and not enlarged.
Bile ducts were not dilated. Hepatic uptake and excretion of
99-mTc-imino diacetic acid were both reduced.
Cholangiography showed a patent extrahepatic bile tree. At week 7 the
patient had to be hospitalized and biochemical variables were
determined on admission. One week later, stools became colored under
ursodeoxycholic acid therapy (50 mg/day), and cholestasis gradually
diminished, but a progressive coagulopathy indicated progression of
hepatocellular dysfunction. The prothrombin time was only 6%
(reference interval 50–100%), resulting in an international
normalized ratio of 35.3 (reference interval <2.0). The activated
partial thromboplastin time was >180 s (reference interval 22–37 s).
Plasma fibrinogen was 4.22 g/L (reference interval 1.80–4.55 g/L). On
the 11th day of hospitalization, at the age of 10 weeks, the patient
died because of a progressive liver failure. A postmortem examination
was carried out. All investigations were performed in accordance with
the Helsinki declaration of 1975 as revised in 1983.
The pedigree of the propositus (no. 1) is presented in Fig. 1
. The parents are extremely consanguineous (father being
maternal grandfather), resulting in an inbreeding coefficient (F) of
0.25 (2). The patient's brother (no. 2) suffered from a
complex congenital heart defect (ventricle septum defect, arteria
pulmonalis stenosis, coarctatio aortae) and a sliding-type hernia
diaphragmatica. He died at the age of 2 years from septicemia after
surgical correction of the congenital defect. Nephew (no. 3), also born
from a consanguineous relation, showed similar skeletal malformations
and was also diagnosed as having Mohr syndrome. Both the propositus'
brother and nephew had normal liver function, and liver enzymes
including ALT were within reference limits.
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Cytogenetic analysis on phytohemagglutinin-stimulated lymphocytes revealed a normal karyotype.
Serum ALT activity of the propositus' parents and his brother and
sisters was within reference limits. At autopsy, liver tissue from the
propositus was obtained and an extract was prepared according to Tsung
(3). ALT activity in the liver extract was undetectable
(<1 U/g of wet tissue, reference interval 50–70 U/g), whereas normal
activities of alkaline phosphatase, -glutamyltranspeptidase, and AST
were found. ALT activities in serum and liver tissue extract were
measured according to the IFCC (4)(5) at
37 °C on a Hitachi 747 analyzer with reagents supplied by Boehringer
Mannheim. In vitro addition of the ALT coenzyme P-5'-P (final
concentration: 4.5 mmol/L) (6) did not result in an
increase of serum or liver tissue extract ALT activity. Presence of
ALT-inhibiting substances in the patient's serum was investigated with
a mixing experiment in which the patient's serum was incubated at
37 °C for 10 min with an equal amount of pooled serum originating
from healthy blood donors. The measured ALT activity of the mixture
corresponded to the theoretically expected activity and thus did
not reveal the presence of an ALT inhibitor in the patient's serum.
Light microscopy revealed portal tracts with hypoplasia of the interlobar bile ducts and a discrete ductular metaplasia surrounded by biliary fibrosis. In numerous hepatocytes accumulation of bile pigments was present. A pseudoglandular arrangement of the hepatocytes occurred. Electron microscopy of the hepatocytes revealed mitochondria with a condensed matrix and a concomitant expansion of the space between the inner and outer membranes. The endoplasmic reticulum showed dilatation of the saccules. These were filled with a medium-dense protein-containing material. Bile pigments were accumulated in the cytoplasm. Postmortem examination of the liver revealed secondary biliary fibrosis. No morphological alterations were observed at the cerebrum, cerebellum, and hippocampus.
Oral–facial–digital syndrome type II (Mohr syndrome) is a rare
malformation syndrome, mainly involving the musculoskeletal system. The
musculoskeletal malformations found in the propositus are diagnostic
for this syndrome. The presence of two nephews with Mohr syndrome
within an extremely consanguineous family is suggestive of an autosomal
recessive inheritance of this condition
(1)(7). Neither liver and bile duct
abnormalities, nor the absence of ALT activity as observed in the
propositus, have been reported to be a part of this syndrome
(1)(7). In the propositus, a hepatocellular
dysfunction was present, as evidenced by the increased liver enzyme
activities in the serum and the present coagulopathy. In contrast, ALT
activity in serum was undetectable. ALT activity is found in many cell
types, but the highest activity is found in liver and kidney tissue
(5). ALT plays a role in the transfer of amino groups from
alanine to 
-ketoglutaric acid. This reaction provides a source of
nitrogen for the urea cycle (5)(8). Earlier,
Cooper et al. (9)(10) demonstrated in a rat
liver model the important role of ALT in homeostasis by its high
capacity to shuttle nitrogen as needed. The lack of ALT could interfere
with this nitrogen shuttling and also deprive the liver of an energy
source. Considering these data, it might not be surprising that liver
failure occurred in this patient.
Enzyme deficiencies theoretically can be caused by an absence of enzyme molecules, by the absence of a coenzyme, or by the presence of inhibitors. Absence of the coenzyme P-5'-P and its amino analog, pyridoxamine-5'-phosphate, and the presence of inhibitors could be excluded in the propositus. Most likely, the propositus had an ALT deficiency due to absence of active enzyme molecules. Earlier, acquired deficiency of ALT was described in hemodialysis patients (11)(12). In these patients, this deficiency has been partly attributed to a deficiency of the ALT cofactor, P-5'-P. Endogeneous inhibitors of ALT have not been described yet. Also, a congenital absence of ALT in serum or tissue has not been reported until now. Thus, primary ALT deficiency is an extremely rare condition.
The isolated finding of ALT deficiency in the propositus suggests that both parents must have been heterozygous for ALT deficiency and therefore points towards an autosomal recessive inheritance. The finding of a nephew with Mohr syndrome but without ALT deficiency suggests that both conditions are unlinked, and that the propositus has inherited Mohr syndrome as a result of the extreme relatedness of the parents. However, the finding of an isolated ALT deficiency in the propositus should not exclude that this ALT deficiency is part of a hitherto undescribed general metabolic disorder or occurs in association with the observed morphological abnormalities in the liver tissue of our patient.
Electron microscopy of the liver showed an endoplasmic reticulum with web-like cannalicular appearance and vesicular dilatation. The changes of the endoplasmic reticulum are suggestive of a defect in protein processing. The mitochondria were characterized by a variable morphology with a tendency to angular widening. In this respect the changes in the mitochondria can be expected to be secondary changes reflecting the condition of the hepatocyte. A marked intrahepatic cholestasis was found, as evidenced by the histological and biochemical analysis (accumulation of bile pigments and increased bilirubin and alkaline phosphatase activity) and nuclear imaging. These morphological findings have not been associated earlier with Mohr syndrome and are hitherto undescribed in the literature. As ALT is mainly a cytosolic enzyme and the morphological changes concern the endoplasmic reticulum and mitchondria, the patient had an undescribed complex congenital syndrome.
In conclusion, we report the first case of a congenital ALT deficiency associated with endoplasmic reticulum and mitochondrial morphological abnormalities in liver tissue in a patient with Mohr syndrome born from an extremely consanguineous relation.
References
-amino acids in free and peptide-linked forms. Scriver CR Beaudet AL Sly WS Valle D eds. The metabolic and molecular bases of inherited disease 7th ed. 1995:1349-1367 McGraw-Hill New York. .
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