Dr. Victor M. Pedro
Department of Clinical Sciences, University of Bridgeport, Bridgeport, Connecticut, U.S.A.
A case study is described of a 6-year-old right-handed Caucasian male diagnosed with Smith-Lemli-Opitz Syndrome. Mother was advanced in age (35) at pregnancy. Delivered at term, but umbilical cord knotted and wrapped around infant’s neck at birth. Feeding tube for cholesterol supplements inserted at age 19 months. Failure to thrive indicative of metabolic syndrome had been observed. Tube removed at age 5 since child began taking cholesterol supplements orally. Global developmental delays first observed at age 6 months. Gross motor and fine motor delays are evident. Medical history is extensive and significant for Dyspraxia of Speech Disorder, Apraxia of Speech Disorder, Ulcers, Mild Mental Retardation, and Autistic Spectrum Disorder. Age 4 weeks, surgery performed for pyloric stenosis. Hospitalized at age 8 months for bacterial pneumonia, anoxia developed, given oxygen. Four subsequent feeding tubes inserted. Received early educational intervention ages 1-3. Experienced pre-school and kindergarten environments ages 4-6. Difficulty observed with peer interactions. Intelligence testing just prior to age 6 revealed most intellectual functioning to fall in the mildly impaired range with significant and global adaptive functioning delays. After four years of special education interventions with no significant improvement in any measurable area of function, a multimodal approach using techniques aimed at facilitating inter-hemispheric communication was provided. At completion of the Cortical Integrative Therapy program, significant improvements were observed in motor coordination, memory, and oral expression.
KEY WORDS: Smith-Lemli-Opitz Syndrome, global developmental delays, cholesterol supplements, Cortical Integrative Therapy
Defects of cholesterol synthesis comprise a heterogeneous group of disorders (Haas D. et al, 2001). Smith-Lemli-Opitz Syndrome (SLOS) is a multiple congenital anomalies and retardation syndrome caused by such a defect (Porter F.D., 2000). SLOS can also be referred to as a sterol disorder (Nissinen M.J. et al, 2000). More specifically, SLOS is an autosomal recessive genetic condition caused by a deficiency of the enzyme 3 beta-hydroxysterol-delta 7-reductase, the final enzyme in the sterol synthetic pathway that converts 7-dehydrocholesterol (7DHC) to cholesterol (Merkens, L.S. et al, 2004). When the final step in cholesterol biosynthesis is disrupted, cholesterol deficiency usually results (Mueller C., et al, 2003). Mutations within the gene DHCR7 produce birth defects and mental retardation of various kind and degree (Nowaczyk M.J. et al, 2003) (Wassif C. A. et al, 1998). Novel mutations are continually being discovered (Jira P.E. et al, 2001) (Patrono C. et al, 2000) (DeBrasi D. et al, 1999). It is a panethnic condition with variable mutation frequencies in different populations (Witsch-Baumgartner et al, 2000).
Multiple congenital malformations associated with SLOS include mental retardation, failure to thrive, craniofacial abnormalities (Antoniades K. et al, 1994), incomplete or ambiguous development of male genitalia (Berensztein E. et al, 1999), limb anomalies, various internal organ abnormalities (Goldenberg A. et al, 2003) precocious puberty (Starck L. et al, 1999) and delayed neuropsychomotor development (Scalco F.B., et al, 2003). In recent years, the SLOS diagnosis is based on the biochemical findings of elevated plasma 7-dehydrocholesterol (7DHC) levels and its isomer 8-dehydrocholesterol (8DHC) (Langius, F.A. et al, 2003) (Starck L., 2000). Affected individuals usually have low plasma cholesterol levels (Pappu A.S. et al, 2002).
Manifestations of SLOS can range from quite severe to very mild clinical presentations (Krakowiak et al, 2000). The phenotype has been redefined to include mildly affected individuals with minor anomalies and developmental delay and severe malformations with pre- and perinatal mortality (Nezarati M.M. et al, 2002). Severely affected individuals (those with the condition formerly referred to as SLOS Type II) have multiple congenital malformations and often are miscarried, stillborn, or die in the first weeks of life. Dysmorphic facial features, microcephaly, second and third toe syndactyly, other malformations, and severe mental retardation are typical in that population. In one study, a 10-year-old boy with SLOS was observed to have an acute gastric volvulus with his stomach definitively fixed to the abdominal wall (Ibanez V. et al, 2001). Mildly affected individuals may have only subtle dysmorphic features and learning and behavioral disabilities.
Much of the damage in the human embryo and developing organism results from low to absent enzyme activity, which accounts for a dysfunctional (non-synthesized) accumulation of both 7-dehydrocholesterol and 8-dehydrocholesterol in brain plasma and other tissues (Wassif C.A. et al, 2003) (Steiner R.D. et al, 2000). In fact, infants with SLOS have reduced activity of the enzyme 7-dehydrocholesterol-7-reductase and accumulate 7-dehydrocholesterol, with the highest concentration in the brain (Bjorkhem I. et al, 2001). The precursor 7DHC can be especially toxic in large concentrations. Further potential damage is associated with the chronic nature of SLOS shown in a patient’s impaired ability to synthesize cholesterol (Shackleton C. et al, 2002). Consequently, the level of plasma cholesterol influences the degree of SLOS severity (Yu H. et al, 2000) (Tint G.S. et al, 1995). If a child affected by SLOS does not receive ongoing care and consultation, including but not limited to receiving cholesterol nutritional supplements from infancy as required, serious and potentially life-threatening consequences can result (Koenig K. et al, 2002). These adverse reactions may include frequent recurrent banal infections, such as adenovirus type 7b, which can produce fatal outcomes in SLOS children and is preventable when a cholesterol supplementation regimen is implemented (Beby-Defaux A. et al, 2001). Clinical benefits have usually been observed in SLOS patients treated with cholesterol supplementation. Benefits include improved growth and a lessening of problem behaviors, but not developmental progress as once assumed (Elias E.R. et al, 1997). In addition, SLOS-affected individuals can have a photosensitivity to ultraviolet light that is reduced by cholesterol supplementation (Azurdia R.M. et al, 2001) sometimes administered with egg yolk (Linck L.M. et al, 2000) or augmented by bile acid replacement (Nwokoro N.A. et al, 1997). Photosensitivity symptomology is sometimes reported in a novel pattern, for instance, the onset of a sunburn-like erythema on sun-exposed skin within minutes of sun exposure, which persisted in most cases for up to 24-48 hours before fading (Anstey A.V. et al, 1999). A high incidence of this particular symptomology has been confirmed (Anstey A.V. et al, 1999). SLOS is also implicated in congenital eye defects (Atchaneeyasakul L.O. et al, 1998) or so-called ocular manifestations (Kretzer F.L. et al, 1981). Links have been established between the neuropathological and ophthalmological. In the case of one three-year-old SLOS-affected boy, the patient was observed to have spontaneous opsoclonus-like eye movements, strabismus, lack of visual following responses, and of optikokinetic reflexes (Fierro M. et al, 1977).
SLOS, especially when untreated, has a specific behavior phenotype resembling autism. In one study, 56 SLOS-affected individuals ranging in age from 0.3 to 32.3 years were evaluated. Of the 56 subjects, 50 (89%) had a history of repeated self-injury; 30 (54%) bit themselves; 27 (48%) head-banged; and 30 (54%) threw themselves backwards in a highly characteristic upper body movement known as “opistokinesis.” Other behaviors typical of SLOS individuals age 10 years and above appear to be a stereotypic stretching motion of the upper body accompanied by hand flicking, sleep disturbances, social and communication deficits (Tierney E. et al, 2001), hypotonia, absence of reflexes, and abnormal crying (Haghiri N. et al, 1999)
David Smith, Luc Lemli, and John Opitz first described SLOS as a genetic multiple congenital anomaly/mental retardation syndrome in 1964. They named the condition RSH after the first initial of the last names of the first three patients ascertained. The clinical characteristics of SLOS have become well established, but for many years the disorder was relegated to the realm of genetic esoterica (Nowaczyk M.J. et al, 1999).
The etiology of SLOS was unknown until 1993. It was discovered that patients with SLOS had low plasma cholesterol levels and accumulated sterol precursors such as 7DHC. Two years later, a cholesterol synthesis defect related to SLOS was discovered (Starck L. et al, 1995). Currently, it is not known why defects in cholesterol synthesis cause congenital malformations. Cholesterol is important in cell membranes, serves as the precursor for steroid hormones and bile acids, and is a major component in myelin. Cholesterol is covalently bound to the embryonic signaling protein sonic hedgehog (Shh), which plays a critical role in several embryologic fields relevant to SLOS (e.g. brain, face, heart, limbs)making cholesterol an essential triggering agent in the early developmental program of the human (Kelley R.L. et al, 1996) (Opitz J.M. et al, 1994). Disorders of cholesterol biosynthesis, exemplified by SLOS, are notable for their severe effects on prenatal development (Kelley R.L., 2000). Tissues (especially brain) deprived of cholesterol or because of deposited sterol precursors and derivatives, develop abnormally and function poorly (Salen G. et al, 1996). In fact, early clinical findings associated with SLOS were rife with brain malformations (Marion R.W. et al, 1987) (Munuz-Calvo M.T. et al, 1981).
SLOS is relatively rare, but occurs most commonly among lighter-skinned peoples in the United States and northern Europe, where incidences have been estimated to be in the 1 in 20,000-40,000 range (Tint G.S. et al, 1994). Advanced childbearing age in the mother, 35 years or older, appears to play a crucial role in engendering congenital development defects such as SLOS (Ginsburg C. et al, 2000). The syndrome is extremely rare in monozygotic twins, with only two cases reported in the literature (Itokazu N. et al, 1992) (Tzouvelekis G. et al, 1991).