comment (1): Mitochondrial Disease in Autism Spectrum Disorder Patients: A Cohort Analysis

[Guest guest]

I perused Weissman et al 2008 (4) yesterday. It's an important

contribution to autism science and to near-future studies and arguments

about mito disorder, disease, and dysfunction. Confusions in

terminology will go on for quite a while, but the new paper expands upon

Poling et al 2006 and thereby helps pave the way for non-genetic

mito-dysfuction (eg, 5) to be openly considered.

As a starting point for further analysis, the mito signs and symptoms

utilized by Weissman et al (4) can be compared to the thoroughly cited

rationale offered by Rossignol and Bradstreet (5). Weissman et al

focused upon criteria presented in two studies published in 2002, and

several of those authors wrote a commentary (1-3).

As mito disorder, disease, and dysfunction are discussed, their

significances bandied about, the politics of autism will intrude. Some

researchers and news media personnel will use and insist upon the

classic concept of mitochondria disorder, a well described pathology

rooted in maternal genetics. However - and this is very important - as

reviewed and elaborated by Rossignol and Bradstreet (5) and suggested by

Weissman et al (4) - many children have signs and symptoms consistent

with mito dysfunction - /*even when classic mito disorder has been

unfindable*. /In other words, a child (indeed, many children) can have

clinically significant mito dysfunction in the absence of classical,

genetic mito disorder.

Cites 1-3 merit our attention because they portray criteria used by

Weissman et al. Furthermore, since there seems to be substantial

evidence that mito dysfunction is not uncommon, we would do well to note

that various pollutants (including but not limited to thimerosal) impair

mito function (5-7; see also 8).

Since most people in developed nations live amidst air, land, and water

pollution, and since pollutants impair mito function, most of us -

perhaps especially infants and toddlers - have suboptimal mito function.

One ramification is that mito-function reference ranges are skewed in an

unhealthy direction. Another ramification is emerging from evidence

reviewed in Poling et al 2006 and in Weissman et al 2008: namely and

especially in the context of each child's intra-body pollutants,

vaccinating children with mito dysfunction increases risk of

vaccination-induced adverse sequelae.

Pre-vaccination screening for mitochondria dysfunction is important. The

mystery of the autism epidemic is not a mystery.

Binstock

Researcher in Developmental & Behavioral Neuroanatomy

1. Neurology. 2002 Nov 12;59(9):1406-11.

Diagnostic criteria for respiratory chain disorders in adults and

children.

Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR.

BACKGROUND: Respiratory chain (RC) disorders are clinically,

biochemically, and molecularly heterogeneous. The lack of standardized

diagnostic criteria poses difficulties in evaluating diagnostic

methodologies. OBJECTIVE: To assess proposed adult RC diagnostic

criteria that classify patients into " definite, " " probable, " or

" possible " categories. METHODS: The authors applied the adult RC

diagnostic criteria retrospectively to 146 consecutive children referred

for investigation of a suspected RC disorder. Data were collected from

hospital, genetics, and laboratory records, and the diagnoses predicted

by the adult criteria were compared with the previously assigned

assessments. RESULTS: The authors identified three major difficulties in

applying the adult criteria:lack of pediatric-specific criteria;

difficulty in segregating continuous data into circumscribed major and

minor criteria; and lack of additivity of clinical features or enzyme

tests. They therefore modified the adult criteria to allow for pediatric

clinical and histologic features and for more sensitive coding of RC

enzyme and functional studies. Reanalysis of the patients' data resulted

in congruence between the diagnostic certainty previously assigned by

the authors' center and that defined by the new general RC diagnostic

criteria in 99% of patients. CONCLUSIONS: These general diagnostic

criteria appear to improve the sensitivity of the adult criteria. They

need further assessment in prospective clinical and epidemiologic studies.

* Research Support, Non-U.S. Gov't

PMID: 12427892

2: Neurology. 2002 Nov 12;59(9):1402-5.

Click here to read

Mitochondrial disorders: a proposal for consensus diagnostic

criteria in infants and children.

Wolf NI, Smeitink JA.

Nijmegen Center for Mitochondrial Disorders, Department of

Paediatrics, University Medical Center Nijmegen, the Netherlands.

BACKGROUND: In 1996 diagnostic criteria were published for adults

with respiratory chain disorders. Modified criteria for children were

also recently proposed. OBJECTIVE: To facilitate and standardize

diagnosis of respiratory chain disorders in children. METHODS: A new

classification has been developed, the Mitochondrial Disease Criteria

(MDC), for the diagnosis of respiratory chain disorders in infants and

children. It considers clinical, metabolic, imaging, and histopathologic

features vs biochemical investigations of skeletal muscle. The criteria

were applied to a group of 30 children. RESULTS: The modified adult

criteria and the MDC gave similar results, with 17 patients having a

definite respiratory chain disorder. No patients reached this category

using the original adult criteria. CONCLUSIONS: The proposed

Mitochondrial Disease Criteria classification allows more precise

definition of clinical and metabolic items and the independent scoring

of muscle biochemical investigations before combining all findings to

determine the overall diagnostic certainty.

* Research Support, Non-U.S. Gov't

PMID: 12427891

3: Semin Pediatr Neurol. 2002 Jun;9(2):151-9.

Current concepts of mitochondrial disorders in childhood.

Borchert A, Wolf NI, Wilichowski E.

Department of Neuropediatrics, University Children's Hopsital,

Heidelberg, Germany.

Respiratory chain deficiencies have long been regarded as rare

neuromuscular diseases mostly originating from mutations in the

mitochondrial genome. Research in the last years has created quite a

different picture. The clinical spectrum has expanded to multiorgan

disease manifestation, with an estimated minimum incidence in children

of 1:11,000. Mutations in the nuclear genome have been discovered in

recent years, thereby adding mendelian genetics to the broadened

spectrum of mitochondrial disease. This review summarizes recent

advances in mitochondrial disorders with a special focus on childhood

presentation and therapeutic approaches that may prove useful in the future.

* Review

PMID: 12138999

4. Mitochondrial Disease in Autism Spectrum Disorder Patients: A Cohort

Analysis

R. Weissman et al.

PLoS ONE 3(11): e3815. doi:10.1371/journal.pone.0003815 [2008]

Background: Previous reports indicate an association between autism

spectrum disorders (ASD) and disorders of

mitochondrial oxidative phosphorylation. One study suggested that

children with both diagnoses are clinically

indistinguishable from children with idiopathic autism. There are,

however, no detailed analyses of the clinical and

laboratory findings in a large cohort of these children. Therefore, we

undertook a comprehensive review of patients with ASD and a

mitochondrial disorder.

Methodology/Principal Findings: We reviewed medical records of 25

patients with a primary diagnosis of ASD by DSM-IVTR criteria, later

determined to have enzyme- or mutation-defined mitochondrial electron

transport chain (ETC) dysfunction.

Twenty-four of 25 patients had one or more major clinical abnormalities

uncommon in idiopathic autism. Twenty-one

patients had histories of significant non-neurological medical problems.

Nineteen patients exhibited constitutional

symptoms, especially excessive fatigability. Fifteen patients had

abnormal neurological findings. Unusual developmental phenotypes

included marked delay in early gross motor milestones (32%) and unusual

patterns of regression (40%). Levels of blood lactate, plasma alanine,

and serum ALT and/or AST were increased at least once in 76%, 36%, and

52% of patients, respectively. The most common ETC disorders were

deficiencies of complex I (64%) and complex III (20%). Two patients had

rare mtDNA mutations of likely pathogenicity.

Conclusions/Significance: Although all patients' initial diagnosis was

idiopathic autism, careful clinical and biochemical assessment

identified clinical findings that differentiated them from children with

idiopathic autism. These and prior data suggest a disturbance of

mitochondrial energy production as an underlying pathophysiological

mechanism in a subset of individuals with autism.

5. Evidence of Mitochondrial Dysfunction in Autism and Implications for

Treatment

A. Rossignol and J. Bradstreet

Am J of Biochem Biotech 4(2): 208-217 , 2008

http://www.scipub.org/fulltext/ajbb/ajbb42208-217.pdf

Classical mitochondrial diseases occur in a subset of individuals with

autism and are usually caused by genetic anomalies or mitochondrial

respiratory pathway deficits. However, in many cases of autism, there is

evidence of mitochondrial dysfunction (MtD) without the classic features

associated with mitochondrial disease. MtD appears to be more common in

autism and presents with less severe signs and symptoms. It is not

associated with discernable mitochondrial pathology in muscle biopsy

specimens despite objective evidence of lowered mitochondrial

functioning. Exposure to environ-mental toxins is the likely etiology

for MtD in autism. This dysfunction then contributes to a number of

diagnostic symptoms and comorbidities observed in autism including:

cognitive impairment, language deficits, abnormal energy metabolism,

chronic gastrointestinal problems, abnormalities in fatty acid

oxidation, and increased oxidative stress. MtD and oxidative stress may

also explain the high male to female ratio found in autism due to

increased male vulnerability to these dysfunctions. Biomarkers for

mitochondrial dysfunction have been identified, but seem widely

under-utilized despite available therapeutic interventions. Nutritional

supplementation to decrease oxidative stress along with factors to

improve reduced glutathione, as well as hyperbaric oxygen therapy (HBOT)

represent supported and rationale approaches. The underlying

pathophysiology and autistic symptoms of affected individuals would be

expected to either improve or cease worsening once effective treatment

for MtD is implemented.

5. Mitochondria and Pollutants including Thimerosal

<http://www.autism.com/medical/research/advances/autism-mitopoll.htm>

6. Air Pollution and Mitochondria

<http://www.autism.com/medical/research/advances/autism-mitoairpoll.htm>

7. Antibiotics and Mitochondria

<http://www.autism.com/medical/research/advances/autism-mitoantibiotics.htm>

8. Mitochondria and autism

<http://www.autism.com/medical/research/advances/autism-mito.htm>

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