BW

Given the main features of autism, motor and speech delay, hypotonia, ataxia, hypereflexia; given her normal carnitines, plasma AA's, urine OA's, karyotype and MRI/MRS head, and taking into consideration the ataxia is probably the most specific finding in her case, I would recommend the
following:

 - Rett syndrome (MECP2) deletion testing and sequencing given the autism
 - ruling out congenital disorders of glycosylation by checking transferrin isolelectric focusing
 - trinucleotide repeat analysis for all the SCA's (spinocerebellar atrophy)
 - lower on the list may be female Duchenne's
 - mitochondrial d/o is definitely on the list as noted in the case so muscle biopsy would be helpful. As a non-invasive test, mtDNA sequencing could be done but in my experience the yield is low unless she clearly fits a known mtDNA disorder
 - lastly, cgh microarray may be helpful to detect small deletions/insertions

Here is a fairly comprehensive list of genetic disorders with ataxia as a feature for which clinical testing is available:

3-Methylglutaconic Aciduria Type 3

Aceruloplasminemia

Acid Sphingomyelinase Deficiency

AHI1-Related Joubert Syndrome

Alexander Disease

Allan-Herndon-Dudley Syndrome

Angelman Syndrome

Argininosuccinicaciduria

ARSACS

Ataxia with Oculomotor Apraxia 1

Ataxia with Oculomotor Apraxia 2

Ataxia with Vitamin E Deficiency

Ataxia-Telangiectasia

Autosomal Dominant Spastic Ataxia

Biotinidase Deficiency

Carbamoylphosphate Synthetase I Deficiency

CEP290-Related Joubert Syndrome

Cerebellar Ataxia, Cayman Type

Cerebellar Hypoplasia

Charcot-Marie-Tooth Neuropathy Type 2B1

Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter

COACH Syndrome

Coenzyme Q10 Deficiency

Dekaban-Arima Syndrome

DRPLA

EIF2B1-Related Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter

EIF2B3-Related Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter

Episodic Ataxia Type 1

Episodic Ataxia Type 2

Episodic Ataxia Type 6

EPM2A -Related Lafora Disease

Familial Hemiplegic Migraine

Familial Hemiplegic Migraine 1

Familial Hemiplegic Migraine 2

Free Sialic Acid Storage Disorders

Friedreich Ataxia

Genetic Prion Diseases

Giant Axonal Neuropathy

Glucose Transporter Type 1 Deficiency Syndrome

Guanidinoacetate Methyltransferase Deficiency

Hartnup Disease

Hereditary Ataxias

Hoyeraal-Hreidarsson Syndrome

Infantile-Onset Spinocerebellar Ataxia

Joubert Syndrome

Joubert Syndrome with Polymicrogyria

Kallmann Syndrome 1

Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation

Marinesco-Sjogren Syndrome

Megalencephalic Leukoencephalopathy with Subcortical Cysts

MERRF

Mevalonicaciduria

Mitochondrial Disorders

Mitochondrial DNA Deletion Syndromes

Mitochondrial DNA-Associated Leigh Syndrome and NARP

Mitochondrial Respiratory Chain Complex III Deficiency, BCS1L-Related

Mucolipidosis I

Multiple Sclerosis

N-Acetylglutamate Synthase Deficiency

Neuronal Ceroid-Lipofuscinoses

NHLRC1-Related Lafora Disease

Niemann-Pick Disease Type C

Ornithine Transcarbamylase Deficiency

Pelizaeus-Merzbacher-Like Disease

PLP1-Related Disorders

POLG-Related Disorders

Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions, Autosomal Dominant 2

Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions, Autosomal Dominant 3

Progressive Myoclonus Epilepsy, Lafora Type

Purine Nucleoside Phosphorylase Deficiency

Pyruvate Dehydrogenase Deficiency

Refsum Disease

Ribose 5-Phosphate Isomerase Deficiency

Sandhoff Disease

Senior-Loken Syndrome

Senior-Loken Syndrome 1

Senior-Loken Syndrome 5

Spastic Paraplegia 6

Spinocerebellar Ataxia Type 1

Spinocerebellar Ataxia Type 2

Spinocerebellar Ataxia Type 3

Spinocerebellar Ataxia Type 5

Spinocerebellar Ataxia Type 6

Spinocerebellar Ataxia Type 7

Spinocerebellar Ataxia Type 8

Spinocerebellar Ataxia Type10

Spinocerebellar Ataxia Type12

Spinocerebellar Ataxia Type13

Spinocerebellar Ataxia Type14

Spinocerebellar Ataxia Type15

Spinocerebellar Ataxia Type17

Spinocerebellar Ataxia Type20

Spinocerebellar Ataxia Type27

Spinocerebellar Ataxia with Axonal Neuropathy, Autosomal Recessive

Spinocerebellar Ataxia with Saccadic Intrusions

Spinocerebellar Ataxia, 16q22-linked

Succinic Semialdehyde Dehydrogenase Deficiency

Sulfocysteinuria

SYNE1-Related Autosomal Recessive Cerebellar Ataxia

TMEM67-Related Joubert Syndrome

Triglyceride Storage Disease with Impaired Long-Chain Fatty Acid Oxidation

Tyrosinemia Type III

Unverricht-Lundborg Disease

X-Linked Sideroblastic Anemia and Ataxia

Many of these can obviously be crossed off immediately but I thought you'd want the full list. I hope this is helpful. Let me know if I can help in any other way.

Joe Thakuria
Mass General Hospital

Dear Joe, Thanks for the differential diagnosis, we really appreciate your time and thoughtfullness. I think there are several possibilites you mention that should be pursued. Thanks again.

One other thing - City of Hope in Duarte, CA offers some molecular testing for autism.

http://www.cityofhope.org/cmdl/NLGN.asp

In addition to NLGN3 and 4, they also offer STK9/CDKL5 mutation analysis (as well as mutation analysis for 6 genes involved in X-linked MR).
Though, our experience at Childrens Hospital has been that the diagnostic yield overall from this testing is low.

Best,
Joe