Infinite Potential Program

Cortical Integrative Therapy in Smith-Lemli-Opitz Syndrome:

Dr. Victor M. Pedro
Department of Clinical Sciences, University of Bridgeport, Bridgeport, Connecticut, U.S.A.

ABSTRACT

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).

CASE REPORT

B.R. is a 6-year-old right-handed male, born at 6 pounds, 10 ounces following a normal (39 weeks) gestation. Mother was of advanced age (35) at pregnancy. Delivered at term, but his umbilical cord was discovered knotted and wrapped around B.R.'s neck at birth. An initial feeding tube for cholesterol supplements was inserted at age 19 months. Failure to thrive, indicative of the metabolic disorder Smith-Lemli-Opitz Syndrome had been observed. Global development delays were first observed at age 6 months. Medical history is extensive and significant for Dyspraxia of Speech Disorder, Apraxia of Speech Disorder, Ulcers, Mild Mental Retardation, and Autistic Spectrum Disorder. Surgery performed on B.R. at age 4 weeks for pyloric stenosis. He was hospitalized at age 8 months for bacterial pneumonia. When anoxia developed, B.R. was given oxygen. Four subsequent feeding tubes were inserted in separate operations. The final feeding tube was removed at age 5 when B.R. became able to take cholesterol supplements orally. B.R. had not completed toilet training at age 5 years, 10 months. He received early educational intervention ages 1-3 and experienced pre-school and kindergarten environments ages 4-6. Difficulties noted with B.R.'s peer interactions and social skills. In kindergarten, B.R. would often "get too close to others" (unable to discern appropriate boundaries) and hit, push, or touch other children indiscriminately. For these reasons, it was nearly impossible for B.R. to "make friends." As a kindergarten student, B.R. was observed to be making academic progress at a slower rate than other children. He could identify a few letters (i.e. 'B' 'E') but was unable to articulate sounds associated with either letter. He was unable to identify any numbers as an early kindergartener, but by the end of the kindergarten year was able to count to 10, clap to the syllables in words, graph data, and participate in a daily writing workshop through drawing and writing. He was also able to name colors blue and green, and point to several distinct colors. B.R. attended kindergarten with an instructional assistant and was receiving several special education services: occupational therapy, physical therapy, and speech therapy. Although he could write his name, he was able to recognize only the first and second letters of his first name. His attention and focus were often deficient and his "language issues" for receptive and expressive language were especially prominent and indicative of severe developmental delays. He spoke in one and two word utterances and possessed a limited vocabulary. B.R. required frequent repetition for directions.

At age 5 years 8 months, B.R. received a complete psychological assessment to obtain a baseline of his cognitive and adaptive functioning skills. He presented as a "very friendly" child, and appeared to enjoy the one-to-one attention he received during the testing sessions. It was apparent that B.R. desired to interact and engage in conversation with the examiner, but due to severe dyspraxia was unable to communicate effectively. He also experienced significant difficulty in understanding some of the standardized verbal testing instructions. Administered the Stanford Binet Intelligence Scales - Fifth Edition (SB-V), a standardized test of intelligence, B.R.'s full-scale intellectual abilities fell in the mildly impaired range, as his overall verbal and visual reasoning skills exceeded only .2% of other children his age. Significant cognitive weaknesses were found (both on verbal and nonverbal assessments) with fluid reasoning, visual spatial reasoning, and on working memory tasks. The evaluator felt that B.R. met the criteria for mild mental retardation, but was also capable of learning.

He received an occupational therapy evaluation at age 5 years, 10 months. When administered the Beery-Buktenica Developmental Test of Visual-Motor Integration, B.R. received a raw score of 6, and a standard score of 63. This score was in the 'very low' range, where average includes a spectrum of 83-117. He had difficulty with visual motor skills, especially with forming and duplicating shapes. He also scored in the 'very low' range when administered VMI tests of motor coordination and visual perception. As part of a three-year educational assessment, B.R. underwent further testing, including the Young Children's Achievement Test (YCAT) and the Kaufman Survey of Early Academic and Language Skills (K-SEALS). In the YCAT, B.R. scored "very poorly" in areas of general information, reading, mathematics, writing, and spoken language. Although he peaked out with a 7 percentile in reading skills, his overall composite was less than 1 percentile, equivalent to a child aged 3 years, 6 months. His K-SEALS scores were even less encouraging. His best result among the subtests was "Numbers, Letters, and Words," where he received a standard score of '80' - ranking him as "well below average" among similarly aged peers. All other subtests were in the "lower extreme" range, and received standard scores between 55 and 69.

METHOD

12-week Cortical Integrative Therapy program

RESULTS

At the conclusion of the 12-week treatment program, B.R. showed considerable gains in his ability to understand directions as noted by an independent examiner, a school psychologist. His overall academic performance, as noted by his classroom teachers and parents, was also significantly improved especially in the areas of reading comprehension, listening skills, oral expression, and global motor development. Of perhaps greater significance, his speech is easier to understand, if slightly slower and more melodic. In addition, his perceptual motor skills and fine motor coordination seem to have substantially improved.

DISCUSSION

Smith-Lemli-Opitz Syndrome is often associated with serious impediment to academic success. B.R. had been stymied throughout his academic career by this disability and his quality of life was severely restricted. But when a multimodal approach using techniques aimed at facilitating inter-hemispheric communication was provided, evidence was produced to indicate that when such techniques are applied, the prospect of indirect neuronal or network modulation occurring as cortical pathways are stimulated becomes a real possibility worthy of further investigation. In addition, there are valuable intangibles effecting quality of life. Prior to participation in Cortical Integrative Therapy, B.R. often grew frustrated with simple homework tasks and academic work. He was reduced to gestures to be understood much of the time. His speech and motor control is now significantly improved, and he is less frustrated while communicating.

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