Division of Child and Adolescent Neurology
Hyaline membranes line the respiratory bronchiole and alveolar ducts of this premature baby's lung. The alveoli are atelectatic (collapsed).
Researchers in pediatric neurology at Mayo Clinic conduct clinical and basic science research into childhood neurological disorders to better understand the origins of epilepsy, learning disabilities and other neurological disorders; and develop new therapies and treatments.
Researchers are engaged in a variety of laboratory and clinical research programs to extend our understanding of the developing nervous system and pathologic processes that underlie neurological disorders in children. The goal isto improve therapies and outcomes for a variety of devastating and debilitating neurologic disorders. Mayo Clinic has expert clinicians and researchers in the areas of:
- Epilepsy (seizures)
- Muscular dystrophy and other muscle disorders
- Multiple Sclerosis
- Cerebral Palsy and spina bifida
- Brain tumors
- Developmental delay
- Movement disorders
- Sleep disorders
- Neurometabolic disorders
Overview of major pediatric neurological disorders
Neuromuscular diseases are a leading cause of disability in children and frequently result from genetic abnormalities that alter the structure and function of muscles and nerves. Recent advances have led to the discoveries of genetic defects that cause several neuromuscular diseases, including those that affect muscle (e.g. muscular dystrophy, congenital myopathy); neuromuscular junction (e.g. congenital myasthesia syndromes); and nerves (e.g. inherited neuropathies and spinal muscular atrophies).
Genetic metabolic diseases
Genetic metabolic diseases are inherited problems with the body's chemistry that affect the way chemical substances in the body are metabolized and energy is generated. Most metabolic disorders are caused by the genetic deficiency of an enzyme needed to transform chemicals. For example, phenylketonuria, or "PKU," is caused by a deficiency of the enzyme phenylalanine hydroxylase, which converts the dietary amino acid, phenylalanine, into another amino acid, tyrosine. The deficiency of phenylalanine hydroxylase leads to the accumulation of a toxic level of phenylalanine and a deficiency of tyrosine, both of which can damage the developing brain and can cause developmental delay.
Other adverse effects of metabolic diseases include seizures, movement disorders, poor growth, muscle weakness, fasting intolerance, and disproportionate illness with simple childhood infections or immunizations.
The most severe metabolic diseases can be deadly if not treated immediately after birth, while others may cause progressive injury or lead to damaging metabolic crises under stressful conditions. Although metabolic diseases individually are rare, more than 1,300 metabolic diseases are recognized and collectively cause an important burden of illness and disability in children.
Movement disorders are a group of neurological conditions characterized by abnormalities in the quality and quantity of spontaneous movements. They range from markedly reduced movement (hypokinetic disorders) to severe constant and excessive movement (hyperkinetic disorders). These disorders affect the speed, quality and ease of movement, and do not lead to weakness or paralysis.
Commonly recognized adult movement disorders include Parkinson's disease and Huntington disease. In children specific diseases are less commonly identified and the disorders are often described by the type of movement observed, such as dystonia, choreoathetosis and hemiballismus. It's believed most adult and pediatric movement disorders result from abnormalities in the basal ganglia, which are groups of neurons deep in the brain linked in circuits and responsible for the planning and execution of movement.
Intellectual Disabilities / Developmental Delay
Intellectual disabilities are defined by development at a rate below average and difficulty in learning and social adjustment. The Individuals with Disabilities Education Act (IDEA) defines intellectual disabilities as: "Significantly subaverage general intellectual functioning existing concurrently with deficits in adaptive behavior and manifested during the developmental period, that adversely affects a child's educational performance."
Intellectual disabilities are not diseases, nor should they be confused with mental illness. Children with intellectual disabilities become functional adults; they are able to learn, but do so slowly, and with difficulty.
Traumatic and Environmental Brain Disorders
Physical brain trauma due to violence and accidents, as well as environmental insults from heavy metals, such as lead and other toxins, are relatively common causes of childhood neurodevelopmental disabilities such as Attention Deficit/hyperactivity Disorders (ADHD), learning disabilities, epilepsy, developmental delay and cerebral palsy. Mayo researchers are studying ways to understand their molecular mechanisms in order to develop better treatments. Basic neuroscience research in this area focuses on changes in synaptic plasticity and gene expression induced by trauma and neurotoxins. An important area of research is the mechanisms for the effect of lead and other toxins on the developing brain. Recent discoveries have identified mechanisms for effects of severe poisoning, such as brain swelling, as well as for more subtle but enduring effects on intelligence.
Deborah Renaud, M.D., studies neurologic manifestations of inherited metabolic disorders in children and adults with particular interest in:
- Peroxisomal disorders.
- Disorders of cobalamin and folate metabolism.
She is also interested in the use of magnetic resonance spectroscopy and x–ray absorption spectroscopy as tools for the investigation of inherited metabolic disorders.
Dr. Renaud is studying magnetic resonance spectroscopy (MRS) as a diagnostic tool for inherited metabolic disorders. To date, MRS has been limited to the assessment for cerebral lactic acidosis in mitochondrial disorders, elevated N–aspartic acid in Canavan's and decreased creatine in creatine synthesis/transport disorders. In collaboration with colleagues in neuroradiology, computer analyses of MR spectra are performed to delineate new diagnostic patterns; to expand the biochemical profiles discernable by spectroscopy; and to better understand the biochemical disturbances present in known disorders.
Dr. Renaud is one of the co–principal investigators for BIOXAS in collaboration with colleagues at the Canadian Synchotron at the University of Saskatchewan. This "state–of–the–art" technology utilizes x–ray radiation to identify the concentration and chemical structure of biochemical substances present in intact cells. Chemical imaging of individual cells to determine the subcellular distribution can also be performed. The BIOXAS group has a particular interest in disorders of iron, sulfur and metal metabolism, both inherited and acquired, which are associated with neurological manifestations.
Peroxisomal Disorders Program
Mayo Clinic Peroxisomal Disorders Program (Grand Rounds webcast)
Suresh Kotagal, M.D., is interested in restless legs syndrome (RLS), frequently under–recognized in children as a cause of insomnia, inattentiveness and daytime fatigue. He is characterizing the clinical features of childhood–onset RLS. He and his team have observed that RLS is inherited in about 75% of subjects; that mothers are more likely to be the affected parents than fathers; and that there is a strong link between childhood RLS and systemic iron deficiency. Studies on the long–term outcome of childhood RLS and clinical treatment trials are being planned.
Dr. Kotagal is also studying narcolepsy–cataplexy, a disabling disorder that affects both adults and adolescents. It leads to severe daytime sleepiness and frequent episodes of muscle weakness in response to emotional triggers. He is evaluating the effectiveness of open–label treatment of this disorder with sodium oxybate. Children with epilepsy frequently manifest sleep complaints, especially difficulty falling asleep and staying asleep. There are no in–depth studies about the nature of these sleep problems. Dr. Kotagal is evaluating prospectively the link between sleep complaints and epilepsy using a questionnaire survey.
Marc Patterson, M.D., is a co–investigator in an NIH–based observational study of Niemann–Pick disease, type C (NPC). The study aims to develop new clinical and laboratory markers of disease progression that will be helpful in designing and executing clinical trials of therapeutic agents. No biomarker currently exists for NPC; and assessment of horizontal saccadic eye movements, which was shown to be robust indicator of neurological dysfunction resulting from NPC in a clinical trial of miglustat (see below), is only available in a few highly specialized centers. Dr Patterson is the principal investigator of an international, retrospective study of miglustat in NPC patients who did not participate in the clinical trial of this drug. Preliminary results support a beneficial effect of the agent. Dr Patterson is also planning a study of the epidemiology of lysosomal storage diseases in Olmsted County with colleagues in Medical Genetics. There are few reliable studies of this area, and this study will utilize the resources of Mayo Clinic to obtain population–based data, which is critical to planning diagnostic strategies and allocation of health care resources for this family of individually rare, but collectively common diseases.
Duygu Selcen, M.D., is interested in myofibrillar and related congenital myopathies. The myofibrillar myopathies (MFMs) have a characteristic morphological signature. At the light microscopic and immunocytochemical level they are associated with progressive myofibrillar destruction and the deposition of composite protein aggregates that immunoreact for desmin, alphaB–crystallin, myotilin, dystrophin, CDC2 kinase, prion proteins, and other proteins. At the ultrastructural level, the myofibrillar degeneration begins at the Z–disk. The elemental change is like that observed in minimulticore disease. The ultrastructural findings provide a clue that the MFMs are caused by mutations in Z–disk related proteins. The investigation tests the hypothesis that mutations in Z–disk related proteins cause MFM and that appropriate expression studies can provide insights into the pathogenesis of the disease. Dr. Selcen has found mutations in desmin, alphaB–crystallin and in other key Z–disk–associated structural proteins including myotilin, ZASP and Filamin C detected in MFM patients.
Mayo Clinic has a Peroxisomal Disorders program, a multidisciplinary clinical and research program for patients with peroxisomal biogenesis defects and X–linked adrenoleukodystrophy, including stem cell transplantation for boys with symptomatic X–linked adrenoleukodystrophy.
Marc Patterson, M.D., focuses his research interests on inborn errors of metabolism. He studied Niemann–Pick type C disease (NPC), an inherited neurodegenerative disorder characterized by an intracellular lipid–trafficking defect with secondary accumulation of glycosphingolipids. Miglustat, a small iminosugar, reversibly inhibits glucosylceramide synthase, which catalyses the first committed step of glycosphingolipid synthesis. Miglustat is able to cross the blood–brain barrier, and is thus a potential therapy for neurological diseases. Dr. Patterson and his colleagues conducted a study to establish the effect of miglustat on several markers of NPC severity. They studied children older than 11 years who had NPC and randomly assigned them to receive either miglustat or standard care for 12 months. He found that Miglustat improved or stabilized several clinically relevant markers of NPC. This is the first agent studied in NPC for which there is both animal and clinical data supporting a disease modifying benefit. (Lancet Neurol. 2007 Sep;6(9):765–72.)
Dr. Patterson and colleagues also studied motor physiology in 15 of the patients participating in the study of miglustat in NPC using accelerometry and surface EMG (sEMG). Tremor amplitude and frequency were quantified using accelerometry, and sEMG was examined for abnormal patterns consistent with various movement disorders. Accelerometric findings correlated with the clinical findings were most consistent with cerebellar outflow tremors. sEMG revealed a mix of dystonic, myoclonic and choreiform movements. These quantitative methods may serve as ancillary measures of disease pathophysiology, markers of change over time, and methods to evaluate efficacy, and side MKeffects, of new treatments as they are developed. (Clin Neurophysiol. 2007 May;118(5):1010–8. Epub 2007 Feb 27.)
Dr. Patterson also studies infantile– and juvenile–onset spinal cerebellar ataxia (SCA), which is associated with expansion of 130 to more than 200 CAG–repeats in the SCA2 and SCA7 genes. Because routine clinical assays for SCA2 and SCA7, which use polymerase chain reaction (PCR) and denaturing PAGE (polyacrylamide gel electrophoresis), will not reliably detect such large expansions, he used an assay to test DNA from individuals more than 10 years of age who had a possible diagnosis of SCA. He concluded that the PCR–blot assay can detect extreme expansion mutations. Routine incorporation of this assay in clinical laboratories may reveal that infantile–juvenile forms of SCA2 and SCA7 are more prevalent than previously recognized.
(Am J Med Genet. 2002 Jul 15;110(4):338–45.)
In collaboration with workers at Mayo and other centers in the US and Europe, Dr. Patterson helped to identify new subtypes of congenital disorders of glycosylation. (CDGs), which are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. Different forms of CDGs can be recognized by altered isoelectric focusing (IEF) patterns of serum transferrin (Tf). Two patients with these symptoms and similar abnormal Tf IEF patterns were analyzed by metabolic labeling of fibroblasts with [2–3H] mannose. Microsomes from fibroblasts of these patients were approximately 95% deficient in dolichol–phosphate–mannose (Dol–P–Man) synthase activity. DPM1, the gene coding for the catalytic subunit of Dol–P–Man synthase, was mutated in both patients. Defects in DPM1 defined a new glycosylation disorder, CDG–Ie. (J Clin Invest. 2000 Jan;105(2):191–8.) In related studies, Dr Patterson and the Mayo team identified the first person in North America with CDG1b (phosphomannose isomerase deficiency), and confirmed the effectiveness of oral mannose in treating this disorder. (J Pediatr. 1999 Dec;135(6):775–81.) Data from this study contributed to an international investigation of the genomic structure of the MPI gene in order to simplify mutation detection. Eight (seven novel) different mutations were found in seven patients with confirmed phosphomannose isomerase deficiency. (Hum Mutat. 2000 Sep;16(3):247–52.)
Kenneth Mack, M.D., Ph.D., conducts research in chronic daily headache (CDH), whichoccurs in 1–2% of children and adolescents. It can evolve from either episodic tension–type headache or episodic migraine, or can appear with no previous headache history. As with other primary headache disorders, treatment is based on the level of disability. Some children and adolescents cope well, but others are markedly disabled by their chronic headaches. As in adults, children and adolescents with CDH are at risk for medication overuse.
CDH is a diagnosis of exclusion, based on a thorough history, normal physical examination, and negative neuroimaging findings. Along with the chronic headaches, children with this condition may have co–morbid sleep problems, autonomic dysfunction, anxiety, and/or depression. Principles of treatment include identifying migrainous components of the headaches, which are treatable with drugs that are effective against migraine, stopping medication overuse, stressing normalcy, using rational pharmacotherapy, and addressing co–morbid conditions. Successful outcomes often involve identifying an appropriate headache preventative, reintegration into school, and family participation in resetting realistic expectations. (Paediatr Drugs. 2008;10(1):23–9.)
Nancy Kuntz, M.D., and her colleagues studied autoantibodies targeting the water channel aquaporin–4 (AQP4), which are are a biomarker for a spectrum of CNS inflammatory demyelinating disorders with predilection for optic nerves and spinal cord (neuromyelitis optica [NMO]). They described the neurologic, serologic, and radiographic findings associated with CNS AQP4 autoimmunity in childhood. They found that aquaporin–4 autoimmunity is a distinctive recurrent and widespread inflammatory CNS disease in children. Their study is published in Neurology. (Neurology 2008 Jul 8;71(2):93–100. Epub 2008 May 28.)
Dr. Kuntz also joined colleagues to study lupus anticoagulant–antiphospholipid syndrome. The team reports the clinical and laboratory findings in a 16–year–old boy with potent lupus anticoagulant who initially presented with recurrent epistaxis, hematuria, and gastrointestinal bleeding. Lupus anticoagulant potently inhibited assay systems for coagulation factors, but levels of factors II, IX, and XI appeared to be decreased (2–5% of mean normal levels). Within 2 weeks after diagnosis, spontaneous subdural hematomas developed. During hemostatic therapy, including plasmapheresis and infusions of recombinant activated factor VII and activated prothrombin complex concentrate, an ischemic stroke developed. Subsequent multifocal recurrent ischemic strokes developed despite immunosuppression. This case shows that lupus anticoagulant or antiphospholipid antibodies can cause both hemorrhagic and thrombotic complications in the same patient and may, in some patients, have multiple target antigens (eg, coagulation factors II, IX, XI). The study was published in the Journal of Pediatric Hematology Oncology. (J Pediatr Hematol Oncol. 2005 Jul;27(7):403–7.)
Duygu Selcen, M.D., recently provided an expert review of myofibrillar myopathies. (Curr Opin Neurol. 2008 Oct;21(5):585–9.) The most important recent advance in the myofibrillar myopathies has been the discovery that mutations in Z band alternatively spliced PDZ–containing protein and filamin C, as well as mutations in desmin, alphaB–crystallin and myotilin, result in similar pathologic alterations in skeletal muscle that are typical of myofibrillar myopathy. Despite the increasing genetic heterogeneity, the clinical and morphologic phenotypes are remarkably homogeneous. The typical clinical manifestation is slowly progressive proximal, distal or both proximal and distal limb muscle weakness. Cardiomyopathy can occur and is sometimes the presenting finding. Peripheral neuropathy also occurs in some patients. In every myofibrillar myopathy, there is abnormal accumulation of an array of proteins at ectopic sites as well as accumulation of degraded myofibrillar proteins forming large aggregates. The key issue now is to analyze the molecular mechanisms underlying the cascade of events that destroy the myofibrillar architecture and trigger the aberrant expression of multiple proteins. Her review found that several disease genes have recently been recognized in myofibrillar myopathies. So far, the disease proteins identified are components of or are molecular chaperones for the Z–disk. In each case, the molecular defect leads to a stereotyped cascade of structural events in the muscle fiber.
Dr. Selcen discovered that mutations in myotilin result in destructive changes in the muscle that starts at the Z–disk, and causes myofibrillar myopathy (MFM) pathology. This discovery now leads to morphologic clues in the diagnosis of myotilinopathies. She also discovered for the first time that mutations in Z–disk alternatively spliced protein (Zasp) causes adult onset muscular dystrophy with MFM pathology. Finally, she discovered for the first time that mutation in Bag3 causes a severe childhood muscular dystrophy associated with cardiomyopathy and respiratory failure. This is the first–ever discovered mutation in the bag family of the proteins. This paper is in press in Annals of Neurology.
Katherine Nickels, M.D. conducts research in pediatric epilepsy, where one of the most concerning risks of withdrawal of medication is the recurrence of seizures. Furthermore, seizures that recur after medication withdrawal may be very difficult to control. According to previous studies, the risk of developing intractable epilepsy following withdrawal of antiepileptic medication is between 1 and 20 percent. However, these studies did not include all seizure types. Neuroimaging and EEGs were not consistently performed to determine whether antiepileptic medications should be withdrawn. Failure to account for abnormalities in neuroimaging and EEG may lead to unwarranted medication withdrawal. Furthermore, the majority of previous studies were not population–based. This could lead to an increased frequency of children who develop intractable epilepsy and may over–estimate the risk of developing intractable epilepsy following discontinuation of antiepileptic medications in seizure–free children with epilepsy. Dr. Nickels is conducting a retrospective chart review to 1) report on the number of children with epilepsy in a population–based cohort who were able to discontinue antiepileptic medications due to seizure–free status; 2) examine the number of children who, after discontinuation of antiepileptic medication due to seizure–free status, developed recurrence of seizures; 3) determine the risk of developing intractable epilepsy following discontinuation of antiepileptic medication in seizure–free children with epilepsy; and 4) determine the risk factors for developing intractable epilepsy following discontinuation of antiepileptic medication in seizure–free children with epilepsy.
Elaine Wirrell M.D., in addition to her collaborative studies with Dr. Nickels, studies the effects of epilepsy on children and teens in terms of their physical activity and body mass index (BMI) percentiles for age. She is evaluating the hypothesis that epileptic children have higher BMI than do their siblings without epilepsy; and what epilepsy–specific factors limit their participation in physical activities. She found that programs that promote exercise in adolescents with epilepsy should be encouraged to improve their physical, psychological, and social well–being. (J Wong, E Wirrell. Physical activity in children with epilepsy compared to their siblings without epilepsy. Epilepsia 2006 Mar;47(3):631–9.)
Dr. Wirrell and colleagues are evaluating the range of diagnoses and the prevalence of previous seizures in children. After studying 127 children referred for a first seizure, they found that diagnostic inaccuracy is common in a first seizure. One quarter of children were incorrectly diagnosed as having a seizure, while the diagnosis of epilepsy was missed in more than one–third of children. (LD Hamiwka, N Singh, J Niosi, E Wirrell. Diagnostic inaccuracy in children presenting with "first seizure": role for a first seizure clinic. Epilepsia 2007 Jun;48(6):1062–6.)