Rett syndrome
Rett syndrome | |
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Specialty | Pediatrics, psychiatry, neurology ![]() |
Rett syndrome, originally termed as cerebroatrophic hyperammonemia,[1] is a rare genetic postnatal neurological disorder of the grey matter of the brain[2] that almost exclusively affects females but has also been found in male patients. The clinical features include small hands and feet and a deceleration of the rate of head growth (including microcephaly in some). Repetitive stereotyped hand movements, such as wringing and/or repeatedly putting hands into the mouth, are also noted.[3] People with Rett syndrome are prone to gastrointestinal disorders and up to 80% have seizures.[4] They typically have no verbal skills, and about 50% of individuals affected do not walk. Scoliosis, growth failure, and constipation are very common and can be problematic.
The signs of this disorder are most easily confused with those of Angelman syndrome, cerebral palsy and autism. Rett syndrome occurs in approximately 1:10,000 live female births in all geographies, and across all races and ethnicities.
In DSM-IV-TR Rett syndrome is listed under the broad category of pervasive developmental disorders, together with the autism spectrum disorders and childhood disintegrative disorder. Some argue that it is misclassified in this group, as it is similar to non-autistic spectrum disorders such as fragile X syndrome, tuberous sclerosis, or Down syndrome where one can see autistic features.[5] Its removal from DSM-5 has been proposed because it has a specific etiology.[6]
It was first described by Austrian pediatrician Andreas Rett in 1966.[7] Huda Zoghbi demonstrated in 1999 that Rett syndrome is caused by mutations in the gene MECP2.[8]
Signs and symptoms
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Initial development is normal. Onset occurs between 6 and 18 months of age.[9] During this time there are subtle developmental deviations and early indicators of Rett syndrome. A period of developmental stagnation is followed by developmental regression where language and motor milestones regress, purposeful hand use is lost, and acquired deceleration in the rate of head growth (resulting in microcephaly in some) is seen. Hand stereotypes are typical, and breathing irregularities such as hyperventilation, breathholding, or sighing are seen in many. Early on, autistic-like behavior may be seen. The infant with Rett syndrome often avoids detection until 6–18 months, owing to a relatively normal appearance and some developmental progress. However, closer scrutiny reveals disturbance of the normal spontaneous limb and body movements that are thought to be regulated in the brainstem. The brief period of developmental progress is followed by stagnation and regression of previously acquired skills. During regression, some features are similar to those of autism. It is, hence, easy to mistakenly diagnose Rett syndrome for autism.[10]
Signs of Rett syndrome that are similar to autism:
- incontinence
- screaming fits
- inconsolable crying
- breath holding, hyperventilation & air swallowing
- avoidance of eye contact
- lack of social/emotional reciprocity
- markedly impaired use of nonverbal behaviors to regulate social interaction
- loss of speech
- sensory problems
Signs of Rett syndrome that are also present in cerebral palsy (regression of the type seen in Rett syndrome would be unusual in cerebral palsy; this confusion could rarely be made):
- possible short stature, sometimes with unusual body proportions because of difficulty walking or malnutrition caused by difficulty swallowing
- hypotonia
- delayed or absent ability to walk
- gait/movement difficulties
- ataxia
- microcephaly in some - abnormally small head, poor head growth
- gastrointestinal problems
- some forms of spasticity
- chorea - spasmodic movements of hand or facial muscles
- dystonia
- bruxism – grinding of teeth
Signs may stabilize for many decades, particularly for interaction and cognitive function such as making choices. Asocial behavior may change to highly social behavior. Motor functions may slow as rigidity and dystonia appear. Seizures may be problematic, with a wide range of severity. Scoliosis occurs in most, and may require corrective surgery. Those who remain ambulatory tend to have less progression of scoliosis.
Cause
Genetically, Rett syndrome (RTT) is caused by mutations in the gene MECP2 located on the X chromosome, and can arise sporadically or from germline mutations. In less than 10% of RTT cases, mutations in the genes CDKL5 or FOXG1 have also been found to resemble it. Rett syndrome was initially diagnosed by clinical observation, but the diagnosis is definitive when there is a genetic defect in the MECP2 gene. In some very rare cases, no known mutated gene can be found suggesting changes in MECP2 that are not identified by presently used techniques or mutations in other genes that may result in clinical similarities.
It has been argued that Rett syndrome is in fact a neurodevelopmental condition as opposed to a neurodegenerative condition. One piece of evidence for this is that mice with induced Rett Syndrome show no neuronal death, and some studies have suggested that their phenotypes can be partially rescued by adding functional MeCP2 gene back when they are adults. This information has also helped lead to further studies aiming to treat the disorder.[11]
Sporadic mutations
In at least 95% of Rett syndrome cases, the cause is a de novo mutation in the child. That is, it is not inherited from either parent. Parents are generally genotypically normal, without a MECP2 mutation.
In sporadic cases of RTT, the mutated MECP2 is usually thought to be derived from the male copy of the X chromosome.[12] It is not yet known what causes the sperm to mutate, and such mutations are rare.
Germline mutations
It can also be inherited from phenotypically normal mothers who have a germline mutation in the gene encoding methyl-CpG-binding protein-2, MECP2.[13] MECP2 is found near the end of the long arm of the X chromosome at Xq28. An atypical form of RTT, characterized by infantile spasms or early onset epilepsy, can also be caused by a mutation to the gene encoding cyclin-dependent kinase-like 5 (CDKL5). Rett syndrome affects one in every 12,500 female live births by age 12 years.
Pontine noradrenergic deficits
Brain levels of norepinephrine are lower in people with Rett syndrome[14] (reviewed in[15]). The genetic loss of MECP2 changes the properties of cells in the locus coeruleus, the exclusive source of noradrenergic innervation to the cerebral cortex and hippocampus.[16][17] These changes include hyperexcitability and decreased functioning of its noradrenergic innervation.[18] Moreover, a reduction of the tyrosine hydroxylase (Th) mRNA level, the rate-limiting enzyme in catecholamine synthesis, was detected in the whole pons of Mecp2-null male as well as in adult heterozygous (Mecp2+/-) female mice.[19] Using immunoquantitative techniques, a decrease of Th protein staining level, number of locus coeruleus TH-expressing neurons and density of dendritic arborization surrounding the structure was shown in symptomatic Mecp2-deficient mice.[19] However, locus coeruleus cells are not dying, but are more likely losing their fully mature phenotype, since no apoptotic neurons in the pons were detected.[19] Researchers have concluded that "Because these neurons are a pivotal source of norepinephrine throughout the brainstem and forebrain and are involved in the regulation of diverse functions disrupted in Rett syndrome, such as respiration and cognition, we hypothesize that the locus coeruleus is a critical site at which loss of MECP2 results in CNS dysfunction." The restoration of normal locus coeruleus function may therefore be of potential therapeutic value in the treatment of Rett syndrome.[18][19]
Midbrain dopaminergic disturbances
The majority of dopamine in the mammalian brain is synthesized by nuclei located in the mesencephalon. The substantia nigra pars compacta (SNpc), the ventral tegmental area (VTA) and the retrorubral field (RRF) contains dopaminergic neurons expressing tyrosine hydroxylase (Th, i.e. the rate-limiting enzyme in catecholamine synthesis).[20][21][22]
The nigro-striatal pathway originates from SNpc and irradiate its principal rostral target, the Caudate-Putamen (CPu) through the median forebrain bundle (MFB). This connection is involved in the tight modulation of motor strategies computed by a cortico-basal ganglia- thalamo-cortical loop.[23]
Indeed, based on the canonical anatomofunctional model of basal ganglia, nigrostriatal dopamine is able to modulate the motor loop by acting on dopaminergic receptors located on striatal GABAergic medium spiny neurons.[24]
Dysregulation of the nigrostriatal pathway is causative from Parkinson disease (PD) in humans.[25] Toxic and/or genetic ablation of SNpc neurons produces experimental parkinsonism in mice and primates.[26] The common features of PD and PD animal models are motor impairments[27] (hypotonia, bradykinesia, hypokinesia).
RTT pathology, in some aspects, overlaps the motor phenotype observed in PD patients.[28][29][30] Several neuropathological studies on postmortem brain samples argued for an SNpc alteration evidenced by neuromelanin hypopigmentation, reduction in the structure area, and even controversial, signs of apoptosis. In parallel, an hypometabolism was underlined by a reduction of several catecholamines (dopamine, noradrenaline, adrenaline) and their principal metabolic by-products.[15] Mouse models of RTT are available and the most studied are constitutively deleted Mecp2 mice developed by Adrian Bird or Rudolph Jaenisch laboratories.[31][32]
In accordance with the motor spectrum of the RTT phenotype, Mecp2-nulls show motor abnormalities from postnatal day 30 that worsen until death. These models offer a crucial substrate to elucidate the molecular and neuroanatomical correlates of a Mecp2-deficiency.[33] Recently (2008), it was shown that the conditional deletion of Mecp2 in catecholaminergic neurons (by crossing of Th-Cre mice with loxP-flanked Mecp2 ones) recapitulates a motor symptomatology, it was further documented that brain levels of Th in mice lacking Mecp2 in catecholaminergic neurons only are reduced, participating to the motor phenotype.[34]
However, the most studied model for the evaluation of therapeutics is the Mecp2-null mouse (totally devoid of Mecp2). In this context, a reduction in the number and soma size of Th-expressing neurons is present from 5 weeks of age and is accompanied by a decrease of Th immunoreativity in the caudate-putamen, the principal target of dopaminergic neurons arising from the SNpc.[35] Moreover, a neurochemical analysis of dopaminergic contents in microdissected midbrain and striatal areas revealed a reduction of dopamine at five and nine weeks of age. It is noteworthy that later on (at nine weeks), the morphological parameters remain altered but not worsen, whereas the phenotype progresses and behavioral deficits are more severe. Interestingly, the amount of fully activated Th (Serine40-phosphorylated isoform) in neurons that remain in the SNpc is mildly affected at 5 weeks but severely impaired by 9 weeks.[35] Finally, using a chronic and oral L-Dopa treatment on Mecp2-deficient mice authors reported an amelioration of some of the motor deficits previously identified.[35] Altogether, these results argue for an alteration of the nigrostriatal dopaminergic pathway in Mecp2-deficient animals as a contributor of the neuromotor deficits.
Treatment
Currently there is no cure for Rett syndrome, but studies have shown that restoring MECP2 function may lead to a cure.[36] One area of research is in the use of Insulin-like Growth Factor 1 (IGF-1), which has been shown to partially reverse signs in MeCP2 mutant mice.[37]
Another promising area of therapeutic intervention is to counter the neuroexcitotoxic effect of increased spinal fluid levels of a neurotransmitter called glutamate and increased NMDA receptors in the brain of young Rett girls,[38] by the use of dextromethorphan, which is an antagonist of the NMDA receptor in those below the age of 10 years. Treatment of Rett syndrome includes:
- management of gastrointestinal (reflux, constipation) and nutritional (poor weight gain) issues
- surveillance of scoliosis and long QT syndrome
- increasing the patient's communication skills, especially with augmentative communication strategies
- parental counseling
- modifying social medications
- sleep aids
- selective serotonin reuptake inhibitors (SSRIs)
- anti-psychotics (for self-harming behaviors)
- beta-blockers rarely for long QT syndrome
- occupational therapy, speech therapy and physical therapy (for children with Rett syndrome).
There is an association of the disease with brain-derived neurotrophic factor (BDNF).[39]
The challenge of developing therapies for MECP2 disorders[40]
Recent studies, funded by the International Rett Syndrome Foundation, demonstrate that neurological deficits resulting from loss of MECP2 can be reversed upon restoration of gene function. These studies are quite exciting because they show that neurons that have suffered the consequences of loss of MECP2 function are poised to regain functionality once MECP2 is provided gradually and in the correct spatial distribution. This provides hope for restoring neuronal function in patients with RTT.
However, the strategy in humans will require providing the critical factors that function downstream of MECP2 because of the challenges in delivering the correct MECP2 dosage only to neurons that lack it, given that the slightest perturbation in MECP2 level is deleterious. Thus, therapeutic strategies necessitate the identification of the molecular mechanisms underlying individual RTT phenotypes and picking out the candidates that can be therapeutically targeted.
The next phase of research needs to assess how complete the recovery is. Clearly, lethality, level of activity, and hippocampal plasticity are rescued, but are the animals free of any other RTT signs such as social behavior deficits, anxiety, and cognitive impairments? Since postnatal rescue results in viability, it will be important to evaluate if even the subtler phenotypes of RTT and MECP2 disorders are rescued when protein function is restored postnatally. This is particularly important given emerging data about early neonatal experiences and their long-term effects on behavior in adults.
Occupational and speech therapy
The symptoms of RTT severely limit individuals from independently taking part in meaningful activities in their day-to-day lives.[41] As a result, most people with this disorder are very dependent on their caregivers in most areas of their lives.[42] Occupational therapists (OTs) try to find ways to encourage these individuals to take part in activities that are meaningful to them, as this has been shown to improve health and well being.[42] The goals of occupational therapy interventions are to maintain or improve the functional abilities of individuals with this disorder. It is important to remember that services for each individual with RTT can differ greatly. OTs work together with clients and their families to help clients achieve their unique goals. OTs not only provide direct services for the client and families, but they can also connect family members to information and resources outside of occupational therapy. Services provided may include but are not limited to: maintaining motor and daily living skills and maintaining cognitive and communication functioning.
Self-care
Some symptoms such as involuntary stereotypical hand movements can make eating a very difficult self-care task for individuals with RTT. One way OTs address this problem is by educating and encouraging caregivers to practice guided feeding. Guided feeding involves having the individual with RTT grasp the spoon and having the caregiver's hand over top of the child's in order to guide the movement of the individual to eat.[42] The purpose of this therapy is to encourage involvement in this important self-care activity, particularly for individuals with severe cases of RTT.[42] Signals such as opening their mouth in preparation for food, rejecting unwanted foods, and spending an increased amount of time watching their helpers, indicates that guided feeding therapy can increase engagement in eating in some cases.[42]
Another way OTs may increase involvement in eating and hand function in general is by making hand splints. Research suggests that hand splints place the hand in a more functional position and prevent repetitive motion; this leads to better finger and spoon-feeding skills.[42] Although fully independent feeding is rare for individuals with RTT, hand splints allow them to become more engaged in eating. Alternatively, active participation can be encouraged through the use of elbow splints, which decrease the repetitive stereotyped arm movements characteristic of RTT. As a result, socialization and interaction with the environment during eating may increase.[42]
Other adaptations to eating include altering the pace of feeding and recommending specific foods and textures that the individual is easily able to swallow.[43] In addition, OT’s provide adaptive devices such as cuffs and loops (to help the individual hold their utensils), large handled utensils that are easier to grasp, and cups with lids to assist with eating and address proper nutrition. In general, all of these therapeutic methods are aimed at improving the quality of the swallowing response and general eating performance.[44] Although parental and self-reports indicate good appetite in most of the population, weight loss is an issue that many individuals with RTT face. This suggests the importance of proper nutritional education for both the individual and their caregivers. This education, along with meal management and planning, may be provided by the Speech and language therapist often in consultation with OT, a nutritionist or dietitian.
The Speech and Language Therapist will assess the person for signs of respiratory compromise and other symptoms of swallowing difficulty, and negotiate management strategies based on balancing and maintaining the persons physical safety, psychological well-being and quality of life. The speech pathologist works with the family, caregivers and client to improve communication and social interaction. This may include using an aac device, eye contact or using their body to communicate their wants and needs to others.
Seating and positioning the individual can also affect how they do daily tasks such as eating, dressing, and grooming. In order for an individual to engage in these tasks, OTs may adjust and modify tables, chairs, and wheelchairs to promote positive interactions within different social environments.[45] OTs are also involved in educating families on various adaptive devices that can promote comfort, ease of use, and safety for children and their caregivers. Some of the commonly used adaptive devices include bath benches, toilet chairs, and movable shower heads.[46] Finally, occupational therapists work with children and their families to develop skills required to brush their teeth and hair, bathe, and dress.[45]
If children with RTT are in school during the day, OTs PTs and speech pathologists can play a role in teaching special education assistants (SEA’s) about the self-care needs of the child. This can include education on feeding techniques that are suitable for the child, proper mechanics of lifts and transfers, as well as toileting techniques and routines.
Productivity
Occupational therapists and physical therapists are involved in helping children with RTT function optimally at school. One of their primary concerns is regarding the child’s seating and positioning in the school environment. As RTT highly impacts a child physically, they often require customized seating, whether it is in the form of a wheelchair or customized chair and desk combinations. The OT or PT consults and provides the equipment necessary for children to be stable and comfortable in their seats. This helps children with RTT stay more focused on their learning and classroom activities, instead of expending energy trying to stay seated upright and balanced.[46] Ultimately, being properly seated may facilitate increased social skills; this is because a child is now able to maintain eye contact with their peers, look around the classroom, and engage with their social environment.[46]
Additionally, OTs, PTs, and speech pathologists are very involved with consulting and educating the child’s teachers and SEAs to better facilitate the child’s learning and care within the school. The team of PT, OT, and speech pathologist may also provide adaptive tools including: boards, adaptive school supplies, and the use of eye-gaze and/or switches to activate educational programs on the computer. These tools may facilitate the individual's communication with other people; they may be able to better communicate their needs, preferences, and choices using these devices.
The team may also suggest certain physical adaptations within the school to better suit the needs of the child. This may include suggestions for classroom setup, adaptations to the washrooms, as well as the installation of ramps, lifts, and/or elevators.
Leisure
Children with RTT need to engage and participate in leisure activities just like typically developing children. Play is the primary activity of childhood and is considered to be both a form of leisure and productivity; it is essential to development as it facilitates cognitive, physical, social, and emotional well-being.[47] Play is an activity with multiple purposes; it provides opportunities for a child to grow and develop, explore, learn, build relationships, and develop interests. Because play is so central to a child's development, therapists try and find ways that allow these children to play. The support team including special ed teacher, OT pt, and speech pathologist work with clients and their family to make sure that the interventions focus on play activities that are meaningful to the child, whether it be arts, music, sports, computer games, and/or maintaining social relationships. There is no set list of the services that are provided in terms of leisure activities, as the team works with the child to find activities that he or she finds enjoyable and important.[46] Some examples of how the team may facilitate play include adapting bicycles, providing switches so that the child can turn on music/video players, and connecting the child and her family to resources and programs within the community.[46]
In addition, some therapeutic activities are regarded as highly enjoyable for children with RTT and can be considered a form of play as well as therapy. One such activity that children with RTT may participate in is aquatic, or swimming therapy. The aims of swimming therapy are to promote relaxation, improve circulation, strengthen muscles, and improve coordination and balance.[41] Aquatic therapy is an enjoyable and relaxing activity for children with RTT, and in some cases therapy has been associated with a decrease in abnormal hand movements and an increase in goal directed hand movements and feeding skills.[41] Examples of other activities that are therapeutic and enjoyable include horseback riding therapy and music therapy.
Communication
Individuals with RTT often do not develop, or lose the ability to communicate through speech.[48] If these individuals cannot communicate with their family and caregivers it makes it very difficult for them to participate in daily activities as they also have severe physical difficulties. Speech pathologists plan communication interventions that aim to increase the skills needed for carrying out self-care, productivity, and leisure tasks. Studies suggest that only twenty percent of the people with RTT had the use of words, and most of these words were used out of context and without meaning.[48] As a result of their lack of spoken language, individuals with RTT can benefit from Augmentative and Alternative Communication (AAC), which are communication methods used in place of speech. Examples of AAC may be written language, body language, and facial expressions.[46] It is within the scope of practice for speech-language pathologists to provide a thorough AAC evaluation taking into consideration all factors such as sensory, motor, kinesthetic, speech, and receptive as well as expressive language in its verbal and non-verbal forms. OTs are consulted in this process, to determine motor or sensory skills and deficits, as well as seating and positioning. This evaluation will result in a recommendation of AAC systems, which often include low-technology, mid-technology and high-technology systems. A speech-language pathologist will also provide therapy to help the client with RTT to access and learn the systems once they are procured, through private funds, school districts, or private/public medical insurance.
Some of the AAC systems common to individuals with RTT include eye-gaze boards, communication boards, switches, or voice output communication devices. Speech-Language Pathologists (SLPs), often with specialized AAC training and knowledge, provide education and training to families, educational teams, and other communication partners on these tools. AAC options are often divided into three levels of technology: no technology, low technology, and higher technology (mid-tech or high-tech, consisting of systems requiring the use of a battery or powercord).[46] The simplest way to communicate is through ‘no technology’ or "unaided" methods in which the individuals with RTT indicates a response (i.e., points, blinks their eyes, raises their eyebrows) to indicate a response. The second type are ‘low technology’ communication systems which often include using pictures, symbols, and/or objects placed on a board. A person then uses eye gaze or finger pointing to show his or her choices. Communication boards can be set up by the SLP and OT in both home and school environments. The third and most complex level of technology is ‘higher technology’. Some of the more commonly used technological devices include voice output systems and computer communication software.[46] Low-technology, mid-technology, and high-technology systems are considered "aided" systems, as they require the use of an object other than one's own body to communicate. The SLP and OT work with the child, as well as the family, caregivers, and school assistants to encourage the child to communicate as much as possible by using all these different tools.
Variants of Rett syndrome
The clinical signs of Rett syndrome typical form are perfectly identified (e.g. see above). In addition to the classical form of Rett syndrome, several «atypical forms» have been described over the years,[49] the main groups are:
- Congenital variant (Rolando variant): in this severe subtype of Rett syndrome, the development of the patients and their head circumference are abnormal from birth.[50] The typical gaze of Rett syndrome patients is usually absent;
- Zappella variant of Rett Syndrome or preserved speech variant: in this subtype of Rett syndrome the patients acquire some manual skills and language is partially recovered around the age of 5 years (that is after the regression phase). Height, weight and head circumference are often in the normal range, and a good gross motor function can be observed.[51][52][53][54][55][56] The Zappella variant is a milder form of Rett syndrome;
- Hanefeld variant or early epilepsy variant. In this form of Rett syndrome, the patients suffer from epilepsy before 5 months of age.[57]
The definition itself of the Rett syndrome has been refined over the years: as the atypical forms subsist near to the classical form (Hagberg & Gillberg, 1993), the "Rett Complex" terminology has been introduced.[58][59]
Prognosis
Males with pathogenic MECP2 mutations usually die within the first 2 years from severe encephalopathy, unless they have an extra X chromosome (often described as Klinefelter syndrome), or have somatic mosaicism.
Male fetuses with the disorder rarely survive to term. Because the disease-causing gene is located on the X chromosome, a female born with a MECP2 mutation on her X chromosome has another X chromosome with an ostensibly normal copy of the same gene, while a male with the mutation on his X chromosome has no other X chromosome, only a Y chromosome; thus, he has no normal gene. Without a normal gene to provide normal proteins in addition to the abnormal proteins caused by a MECP2 mutation, the XY karyotype male fetus is unable to slow the development of the disease, hence the failure of many male fetuses with a MECP2 mutation to survive to term. Females with a MECP2 mutation, however, have a non-mutant chromosome that provides them enough normal protein to survive longer. Research shows that males with Rett syndrome may result from Klinefelter's syndrome in which, the male has an XXY karyotype.[60] Thus, a non-mutant MECP2 gene is necessary for a Rett's-affected embryo to survive in most cases, and the embryo, male or female, must have another X chromosome.
There have, however, been several cases of 46,XY karyotype males with a MECP2 mutation (associated with classical Rett syndrome in females) carried to term, who were affected by neonatal encephalopathy and died before 2 years of age.[61] The incidence of Rett syndrome in males is unknown, partly owing to the low survival of male fetuses with the Rett syndrome-associated MECP2 mutations, and partly to differences between signs caused by MECP2 mutations and those caused by Rett's.[62]
Females can live up to 40 years or more. Laboratory studies on Rett syndrome may show abnormalities such as:
- EEG abnormalities from 2 years of age
- atypical brain glycolipids
- elevated CSF levels of beta-endorphins and glutamate
- reduction of substance P
- decreased levels of CSF nerve growth factors
A high proportion of deaths are abrupt, but most have no identifiable cause; in some instances death is the result most likely of:
- spontaneous brainstem dysfunction
- cardiac arrest
- seizures
- cardiac conduction abnormalities - abnormally prolonged QT interval on ECG
- gastric perforation
References
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Rett initially called this syndrome cerebroaatrophic hyperammonemia, but the elevated ammonia levels in the bloodstream were later found to be only rarely associated with this condition (can Acker, Loncola, & Can Acker, 2005).
- ^ "Rett syndrome" at Dorland's Medical Dictionary
- ^ Andrew S. Davis (25 October 2010). Handbook of Pediatric Neuropsychology. Springer Publishing Company. ISBN 082615736X.
The cases in his report shared the characteristics of stereotyped hand-wringing movements, MR, autistic symptoms, ataxia, cortical atrophy, and elevated ammonia in the blood.
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