Identification of a novel DHCR7 mutation in a Korean patient with Smith-Lemli-Opitz syndrome

Smith-Lemli-Opitz syndrome is a unique malformation syndrome characterized by a defect in cholesterol biosynthesis, which is very rare among populations in Middle and East Asia. The authors identified compound heterozygous mutations ([p.Arg352Trp] + [p.Lys376ArgfsX37]) in a Korean girl with clinical and laboratory features typical of Smith-Lemli-Opitz syndrome. The Lys376ArgfsX37 mutation is a novel mutation, and to the best of the authors' knowledge, this is the first report of a clinically and genetically confirmed case of Smith-Lemli-Opitz syndrome in Korea.     

Cholesterol metabolism and suicidality in Smith-Lemli-Opitz syndrome carriers

OBJECTIVE: The authors examined the relationship between cholesterol metabolism and suicidality in carriers of Smith-Lemli-Opitz syndrome and their families. This population has a partial deficiency in 7-dehydrocholesterol reductase (DHCR7), the enzyme that catalyzes the last step in cholesterol biosynthesis. METHOD: Suicidal behavior, depression, misuse of alcohol and drugs, and family history of psychopathology, including attempted or completed suicide, were assessed by structured interview in 51 carriers of Smith-Lemli-Opitz syndrome and 54 matched comparison subjects. RESULTS: There were significantly more suicide attempters and completers among the biological relatives of Smith-Lemli-Opitz syndrome carriers than comparison subjects, but family history of psychopathology did not significantly differ between the groups. More suicide attempts were reported among Smith-Lemli-Opitz syndrome carriers than among the comparison subjects. CONCLUSIONS: These results, based on a unique study design, provide additional evidence supporting the relationship between cholesterol metabolism and suicidal behavior.     

Infantile spasms in monozygotic twins with Smith-Lemli-Opitz syndrome type I]

Monozygotic twins with Smith-Lemli-Opitz syndrome who developed infantile spasms were presented. They were the result of the first full-term pregnancy of non-consanguineous parents. They had following abnormalities: marked growth and developmental retardation, congenital heart disease, light brown hair which is rare in Japanese, small dolichocephaly, hypertelorism, anteverted nostrils, micrognathia, hypospadias and shawl scrotum. The cranial MRI showed the delayed myelination of occipital lobe. As far as we could review published reports, we were unable to find other report on monozygotic twins having the Smith-Lemli-Opitz syndrome.     

Inherited disorders of cholesterol biosynthesis

Defects of cholesterol biosynthesis comprise a heterogeneous group of disorders, most of which have only been recently described and more are likely to follow in the near future.Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) are due to allelic defects in mevalonate kinase, an enzyme located proximally in the pathway of cholesterol and nonsterol isoprene biosynthesis. Clinically, patients affected with these disorders present with recurrent febrile attacks. This is the only manifestation in most patients with HIDS, and, in the case of classical mevalonic aciduria, is part of a severe multisystemic disease, including malformations, severe failure to thrive and neurological abnormalities. The other recognized defects of cholesterol biosynthesis are due to enzyme defects located distally in the pathway beyond the branching points of nonsterol isoprene biosynthesis and solely affecting cholesterol biosynthesis. Patients with these disorders all present with complex malformation syndromes involving different organ systems. The main characteristics of CHILD syndrome and Conradi-Huenermann syndrome are skeletal defects and ichthyosiform skin involvement. Smith-Lemli-Opitz syndrome and desmosterolosis are generalized malformation syndromes involving many different organs including the central nervous system.The diagnosis of MVA and HIDS is based on determination of mevalonic acid in urine followed by determination of enzyme activity, whereas the search for the distally located defects of cholesterol biosynthesis requires sterol analysis in blood or tissues by GCMS.Rational therapeutic approaches have been described for HIDS, MVA and Smith-Lemli-Opitz syndrome.     

MRI in Smith-Lemli-Opitz syndrome type I

We describe a single case of a polymalformational syndrome in which the MR findings were of great help in the final diagnosis of Smith-Lemli-Opitz syndrome (SLOS) type I. MRI was performed for evaluation of the brain morphology since the clinical and laboratory findings were suggestive but not unequivocally indicative of SLOS. MRI findings of frontal lobe hypoplasia, cortical migration defect, and abnormalities of median line structures prompted the final diagnosis of SLOS. Received: 18 May 1995     

A family with three sisters with the 4p- syndrome, originally reported as suffering from the Smith-Lemli-Opitz syndrome

ABSTRACT. The authors further describe investigations of a family originally reported by Bundey & Smyth in 1974 with a diagnosis of the Smith-Lemli-Opitz syndrome. Chromosome studies performed for the fourth time revealed that the mother had a presumptive t(4;22) translocation. The importance of reviewing earlier diagnoses, including repeating the chromosome studies if indicated, in order to arrive at a more accurate diagnosis is stressed. It is also important to provide the cytogenetics laboratory with clues to any possible clinically-recognisable chromosome syndrome, and to be prepared to examine the chromosomes of the parents of the affected case, even if the patient's karyotype appears normal. In this particular family, the correct diagnosis in the affected girls led to a realization that their brother had a 50% risk of producing unbalanced offspring.     

Clinical case: vermis hypoplasia with features of Smith-Lemli-Opitz syndrome

This article attempts to describe a very unusual case of a boy aged 15, who has had intractable epileptic phenomena, mental retardation, megalocephaly, micrognathy, syndactyly, small tongue, hypoplastic genitalia, gynecomasty, obesity, and slight left body hemiatrophy. Neurologically the patient has had hypotonia of the lower limbs, cerebellar dysfunction including horizontal nystagmus, bilateral intention tremor, dysdiadokokinesia, gait ataxia. The clinical investigation revealed low plasma cholesterol and hypoplasia of the vermis in MRI. The epileptic phenomena were intractable and polymorphous. One should have thought that this is an unusual case of Smith-Lemli-Opitz syndrome associated with features of Joubert syndrome.     

CLINICAL CASE: VERMIS HYPOPLASIA WITH FEATURES OF SMITH-LEMLI-OPITZ SYNDROME

This article attempts to describe a very unusual case of a boy aged 15, who has had intractable epileptic phenomena, mental retardation, megalocephaly, micrognathy, syndactyly, small tongue, hypoplastic genitalia, gynecomasty, obesity, and slight left body hemiatrophy. Neurologically the patient has had hypotonia of the lower limbs, cerebellar dysfunction including horizontal nystagmus, bilateral intention tremor, dysdiadokokinesia, gait ataxia. The clinical investigation revealed low plasma cholesterol and hypoplasia of the vermis in MRI. The epileptic phenomena were intractable and polymorphous. One should have thought that this is an unusual case of Smith-Lemli-Opitz syndrome associated with features of Joubert syndrome.     

Developmental sensitivity of associative learning to cholesterol synthesis inhibitors.

Patients with Smith-Lemli-Opitz syndrome, a genetic disorder associated with severe mental retardation, are unable to convert 7-dehydrocholesterol to cholesterol. Treatment of rats with agents that block cholesterol synthesis produces a sterol profile reminiscent of Smith-Lemli-Opitz patients i.e., low levels of cholesterol accompanied by the appearance of its immediate precursor 7-dehydrocholesterol. In previous work, chronic inhibition of cholesterol synthesis in just-weaned rats impaired acquisition of the classically conditioned eyeblink response. The present study had two primary goals--(1) to determine whether the learning impairment depended on the age in which treatment was initiated; and (2) to determine whether the deficit was associative or due to performance factors. Consistent with earlier work, acquisition of the eyeblink conditioned response was impaired when the 30-day treatment was initiated on postnatal day (PND) 21. Reactivity to acoustic stimuli and to eyelid stimulation were normal, suggesting that the learning impairment was associative in nature. The learning impairment was transitory; acquisition was normal when evaluated 30 days after the cessation of treatment. When treatment was initiated 30 days after weaning (PND 51), acquisition of the eyeblink response was normal. However, brain sterols of young adult rats were less affected than those of just-weaned rats. Thus, there is a developmental sensitivity to cholesterol synthesis blocking agents both in terms of their effects on brain sterols and new motor learning.     

Autism: the role of cholesterol in treatment

Cholesterol is essential for neuroactive steroid production, growth of myelin membranes, and normal embryonic and fetal development. It also modulates the oxytocin receptor, ligand activity and G-protein coupling of the serotonin-1A receptor. A deficit of cholesterol may perturb these biological mechanisms and thereby contribute to autism spectrum disorders (ASDs), as observed in Smith-Lemli-Opitz syndrome (SLOS) and some subjects with ASDs in the Autism Genetic Resource Exchange (AGRE). A clinical diagnosis of SLOS can be confirmed by laboratory testing with an elevated plasma 7DHC level relative to the cholesterol level and is treatable by dietary cholesterol supplementation. Individuals with SLOS who have such cholesterol treatment display fewer autistic behaviours, infections, and symptoms of irritability and hyperactivity, with improvements in physical growth, sleep and social interactions. Other behaviours shown to improve with cholesterol supplementation include aggressive behaviours, self-injury, temper outbursts and trichotillomania. Cholesterol ought to be considered as a helpful treatment approach while awaiting an improved understanding of cholesterol metabolism and ASD. There is an increasing recognition that this single-gene disorder of abnormal cholesterol synthesis may be a model for understanding genetic causes of autism and the role of cholesterol in ASD.     

Mineralization of the basal ganglia detected by CT in Hallervorden-Spatz syndrome

We studied a patient with autopsy-proven Hallervorden-Spatz syndrome (HSS) and the previously unreported finding of high-density lesions in the basal ganglia on CT. The diagnosis of HSS should be considered in a patient with dystonia and basal ganglia mineralization on CT.     

Is the routine CT head scan justified for psychiatric patients? A prospective study.

Thirty-four psychiatric patients, assessed for a physical illness that was missed during diagnosis, underwent a CT scan. After investigation, the diagnosis of 14 patients changed from a functional to an organic illness. In nine patients, the CT scan was reported to be abnormal, and yet only two were diagnosed as having an organic syndrome. In seven patients, the CT scan was normal but the patients had an undisputed organic brain syndrome. These findings indicate that the use of CT scans should be restricted to cases in which the diagnosis is seriously in question. The clinical findings should dictate the use of CT scans either to clarify or to complement them.     

The prevalence of computed tomographic abnormalities of the cerebrum in 100 consecutive children symptomatic with the human immune deficiency virus

Qualitative analysis of 100 consecutive computed tomographic (CT) studies of the brain in children with symptomatic but untreated acquired immunodeficiency syndrome was performed. After excluding children with associated medical illnesses that might confound the diagnosis of encephalopathy or alter brain structure, an abnormality of at least one of the measures of ventricular size, cortical atrophy, white matter attenuation (leukoaraiosis), or cerebral calcification was found in 86% of the patients studied. Ventricular enlargement was the most common abnormality, followed by cortical atrophy, leukoaraiosis, and cerebral calcification. Cerebellar atrophy was an unexpected but relatively common finding in 12% of the children. Sixty-five percent of the children were encephalopathic at the time of evaluation. All 16 children with cerebral calcification were encephalopathic and had acquired human immunodeficiency virus (HIV) through vertical transmission. Encephalopathic children were significantly younger and had significantly greater abnormality ratings on each CT measure when compared with the nonencephalopathic children. Discriminant analysis using age and the qualitative CT measures was applied as a method to identify the presence of encephalopathy. CT measures proved to have a specificity and a sensitivity of only 76%. We conclude that abnormalities of cerebral structure are seen in a high percentage of children symptomatic with HIV. Although most of the children are encephalopathic, CT abnormalities are seen in children without encephalopathy, suggesting presymptomatic brain disease. The presence of cerebral calcification on CT suggests in utero infection with HIV and the presence of encephalopathy. Although not diagnostic of encephalopathy, routine use of CT in pediatric patients with acquired immunodeficiency syndrome may add significant additional information about the mode of HIV transmission and potential presymptomatic brain disease.     

Computerized tomography. An adjunct to early diagnosis in the cauda equina syndrome of ankylosing spondylitis

This article describes a case of the cauda equina syndrome associated with ankylosing spondylitis. The typical myelographic features and the computerized tomography (CT) scan of the lumbar spine are included. The CT scan may aid in elucidating the pathogenesis of the disorder.     

Ophthalmoplegia, ataxia and hyporeflexia (Fisher's syndrome). With a midbrain lesion demonstrated by CT scanning

This report concerns a patient with ophthalmoplegia, ataxia and hyporeflexia (Fisher's syndrome) with a lesion in the midbrain tegmentum demonstrated by computerized-tomography (CT) scanning. Spontaneous recovery was almost complete 1 month after the onset. Based upon its strategic location, it is suggested that the lesion can explain the findings in the patient. The CT finding, if confirmed, will necessitate a reconsideration of our current pathogenetic views about Landry-Guillain-Barré syndrome in general and Fisher's syndrome in particular.     

A review of the EEG literature on Ganser's syndrome

Ganser's syndrome has been classified as a histrionic disorder, a psychotic illness, a dissociative disorder, a factitious disorder, and an organic illness. The possibility of an underlying organic component to Ganser's syndrome is often implicated. A case which includes CT scan and EEG tests is presented and the EEG data in patients with Ganser's syndrome are reviewed. The majority of EEG data was not suggestive of any specific organic illness.     

Is autophagy an elective strategy to protect neurons from dysregulated cholesterol metabolism?

The balance of autophagy, apoptosis and necroptosis is crucial to determine the outcome of the cellular response to cholesterol dysregulation. Cholesterol plays a major role in regulating the properties of cell membranes, especially as regards their fluidity, and the regulation of its biosynthesis influences the shape and functions of these membranes. Whilst dietary cholesterol can easily be distributed to most organs, the central nervous system, whose membranes are particularly rich in cholesterol, mainly relies on de novo synthesis. For this reason, defects in the biosynthesis of cholesterol can variably affect the development of central nervous system. Moreover, defective synthesis of cholesterol and its intermediates may reflect both on structural cell anomalies and on the response to inflammatory stimuli. Examples of such disorders include mevalonate kinase deficiency, and Smith-Lemli-Opitz syndrome, due to deficiency in biosynthetic enzymes, and type C Niemann-Pick syndrome, due to altered cholesterol trafficking across cell compartments. Autophagy, as a crucial pathway dedicated to the degradation of cytosolic proteins and organelles, plays an essential role in the maintenance of homeostasis and in the turnover of the cytoplasmic material especially in the presence of imbalances such as those resulting from alteration of cholesterol metabolism. Manipulating the process of autophagy can offer possible strategies for improving neuronal cell viability and function in these genetic disorders.     

Thalamic stroke: correlation of clinical symptoms, somatosensory evoked potentials, and CT findings

We studied 18 patients with a single ischemic thalamic lesion, who had somatosensory disturbances and/or central pain in the opposite hemibody, by correlating their clinical symptoms, somatosensory evoked potentials (SEPs), and computed tomography (CT) findings. Patients were divided into three groups: (1) those with somatosensory deficits, central pain, and abnormal SEPs, which comprised two thirds of the patients (classic thalamic pain syndrome), (2) those with somatosensory deficits, no central pain, and abnormal SEPs (analgetic thalamic syndrome), and (3) those with almost normal sense perception, central pain, and normal SEPs (pure algetic thalamic syndrome). CT evidence of a paramedian or anterolateral thalamic lesion might be an indicator for the development of central pain, because these types of infarctions occurred only in patients with the classic thalamic syndrome or the pure algetic thalamic syndrome. The differentiation of the thalamic syndrome into three subtypes is of prognostic value, because patients with a loss of cortical SEPs and a posterolateral ischemic thalamic lesion on the CT scan probably will not exhibit central pain.     

Traumatic lesions of the brain stem: electroencephalographic and computer-tomographic follow-up study in the acute phase

Combined EEG and CT examinations were carried out in a prospective study of 20 patients with acute midbrain syndromes. After head injury EEG and CT examinations were repeated at intervals no longer than 3 days. In 13 younger patients alpha waves and spindles occurred during the first few days after injury even in a patient with a thalamo-cortical tract lesion as visualized in CT scan. CT revealed ponto-mesencephalic haemorrhage in 2 patients and ponto-mesencephalic oedema in two others. Increase and decrease of oedema correlate well with the EEG changes: at the time of the most pronounced brain oedema (days 3-12) the most serious EEG changes are found. A midbrain syndrome following head injury implies a poor prognosis.