User:Etchevers/Notebook/Conference notes/2008/07/04

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Notes for Berder 12 - second day

Laurent Pasquier with Sylvie Odent

  • VACTERL association

VATER = vertebral, anal, esophageal atresia/fistula tracheo-esophageal, and radial and renal anomalies. Became VACTERL with limb – radial in particular, C for cardiac malformations. Bit study in 1996 by Rittler et al. found 103 isolated cases, remove C from acronym? Superimposed also with diaphragmatic hernia, 15 hemivertebra out of 26 anomalies. How many malformations to fall into VATERL spectrum? me objection in the room because there can be, after all (this means, thumb duplication), associated with hemivertebrae and/or fusion; Fanconi (microcephaly, cancer, hemivertebrae); CHARGE; 22q11 deletion

  • Murine models: Gli2 (no cardiac/renal anomalies), Gli3 (no cardiac/renal/tracheo-oesophagean anomalies), Shh (not bad but no vertebral column at all)

VACTERL- hydrocephaly – stenosis of Sylvian aqueduct first described. Associated with Fanconi anemia. AR as well as recessive X-linked. L Faivre et al. Am J Med Genet 2005 & Rhombencephalosynapsis (fusion of rhombencephalon dorsal?) with VACTERL + HC observation. Unilateral radial defect once (extra thumb bit). Association in 7/60 cases. Linked indeed to a dysplasia of Sylvian aqueduct as seen by fetopath (rosettes in histo). Not really a stenosis. One case of recurrence. That one didn’t have HC. And no association with Fanconi anemia. If TBX1 is associated with overlapping DiGeorge syndrome (directly binding the FGF10 promoter? Tbx5 binds 7 kb upstream of FGF10 in limb near a b-catenin-activated site, cf Agarwal 2003), Tbx3 with ulnar-mammary, Tbx5 in Holt-Oram (heart-limb) what about Tbx6? It’s not expressed anywhere outside of PSM and somites, so not possible.

Didier Lacombe

  • Syndrome de Goldenhar

= Oculo-auriculo-vertebral 1/5600 births, 3:2 ratio of men, but heterogeneous both genes and phenotypes. Hemifacial microsomia in 2/3 of cases; lesions mostly all on same side. External ear malformations (microtie), but also sinus problems. Benign dermoid tumor of eye in conjunctive, upper eyelid coloboma or other anomalies (25%), blepharophtosis. Tendency to right side? Ear anomalies can be bilateral up to 50%, transmission (but also perception) deafness in 50-85% of cases. Sometimes ear on the cheek altogether. External ear has not “migrated” up in front of the otic vesicle. Eur J Med Genet 2008 OAVS microtia classification for 53 patients. Many of these are small as well (13%), 30-60% vertebral problems. 20% cardiac malformations, CNS anomalies 10%, 10% mental retardation. Mostly sporadic. 2% familial history +. AD “favorisé” but incomplete penetrance. AR reported. If familial, fewer symptoms in other “affected” members. Can get equivalent with thalidomide/retinoic acid, maternal diabetes, trisomy 18, trisomy 22. Linkage to 14q22.3 Kelberman et al 2001 BAPX1 unequal allelique expression – epigenetic dysregulation Fischer 2006 Mutations/variations in TCOF1 (Su et al 2007)

  • HOXA2 in microtie Iranien autosomic recessive Alasti et al 2008 – cleft palate and dysmorphie. This is a special form of microtie rather than a real Goldenhar, says another member of the audience.

Caroline Rooryck Thambo

  • cytogeneticist on her PhD project about Goldenhar with Didier. Have 60 patients, placing on pangenomic 44K, 105K, 244K for SNP analysis? or gene copy dosage. Looking at candidate genes. 3 patients have 1-2Mb deletions/duplications, 5 of them have dup or del of 10-200kb regions with just one or two genes.
  • A de novo deletion 2.3 Mb in 12p13.3 with lots of genes.

This same Caroline will do the CGH microarray analysis (or the 44K Agilent chips?) on Nicolas’ cohort of non-mutated micro/anophthalmias.

Wildervank syndrome –cervico-oculo-acoustic

Perception deafness, internal ear; Klippel-Feil anomaly and Duane syndrome. Anomalies cranio-spinal: vermian hypoplasia, hydrocephaly T... has costal synostes, anomalies of cervical rachis, oculomotor problems (Duane syndrome). AD transmittion, more girls reported. Sylvie Manoeuvrier has excluded SALL4, also high resolution karyotype, as well as 44K Agilent pangenomic. Looked for microdeletion 8q12.2-q21.2 because of the Duane association – continuous gene syndrome that has been published.

===Sandrine Marlin, with Marie Gonzales=== and others: Trousseau and Cochin

  • Mega-bladder
  • Familial: anamnios, megabladder, bilateral renal dysplasis, rachischisis posterior in XY IMG at 24sa. Dysmorphie b/c of anamnios. Hexadactyly on G, pieds en piollet. Polykystic kidneys, irregular of C5-C6, cervical ribs.
  • Madame: dysmorphic, camptodactyly, malpositioned feet, hard to raise shoulders. Pregnant when had asked for radio – not known! Menton proeminent, pointu. “Condensation” cranienne. Retractions en doigts, but fusion in long bones, very long bones in hands/feet.

2nd fetus XY: myelomeningocoele, bilateral postaxial polydactyly hand and feet (Marie), somewhat prognathe.

  • Mother has a “faux sens” on Filamin A gene in htz, so did the fetuses. Looking for RNA in fetal tissues. What about girls’ phenotype? The mother didn’t know she was symptomatic, nor her mother/brother. Very few cases, difficult for genetic counseling.
  • Didier says thinks of “OPD”

Hubert Journel

  • Genetics of NTD
  • Closure points – perhaps needs to take a look at my old presentation

Talks about highly heterogenetic: trisomies 21, 13, 18, 9, 6, 14, 15, 20, triploidies and monosomie X (Turner) has been described. These are for the prenatal forms. For neonatal forms 2-10% of NTD, but still plenty of chromosomal anomalies

  • Some recurrences for chromosome 13, as well as dup 2p24 with GC7 and DDEF12.
  • Lots of genes that have been associated at least once with NTD, even longer for mice KO’s. Eg. FOXN1 in human athymic Nude/SCID fetus.
  • Some have looked at choline intake and gene polymorphisms in California population. (CHKA). Rick Finnell, also Cofilin1, small augmentation of risk factor.

VANGL1 in 3/137 cases (April 2007)

  • Tour de genome, CGH array, NTD – not really good genes coming out. &p22 Meox2, Twist1? 10q25.3 with FGFR2 and neighbors.

NTD and syndromes with vertebral implications have discussed above.

  • Folate metabolism: MTHFR polymorphisms for methylation and transcription of gene.
  • Possibility of antibodies against MTHFR or other folate receptors Cf Rothenberg NEJM 2004 but almost no publications since. Theory is that folate supplementation overrides and saturates blockage by antibodies. Checking folinic acid 5mg supplementation to get around necessity of methylating the folate (or something like that).

Cedric Le Caignec from Nantes

  • Chromosomal anomaly
  • Small, hypotonia, hyperlaxité. Wide forehead, imperforation des canaux lachrymaux. CIV muscular and CIA, Wolff-Parkinson-White syndrome
  • Vertèbres “ailes de papillon” Karyotype translocation between 1p and 6q t(1;6)(p13;q16) de novo. Lien avec phenotype observé – attention check sonde JAG1 – indeed also had a deletion de novo as shown y BAC RP5-1099D15. Cries of “bravo, Albert” from the room. Most liver markers are normal, no eye manifestations. But the vertebral anomalies ok. Use CGH oligoarray 44K to see if deletion also took out BMP2 on chromosome 20 (yes – deletion about 5Mb). Yet ANOTHER unbalanced deletion 6q16 of 8.26 Mb also found.
  • Reminded him of someone with WPW with deletion on 20p12 saw in poster where boy and mother have 2.33Mb, but only the boy presented (also mental retardation); second case with 1.3Mb deletion kid had CIA, difficulties to eat and language retard defect. One gene already known = PRKAG2 with two mutations known, for the rare familial forms. Most sporadic forms are unexplained. Proposes a given member of growth factor family (almost obvious) is a good candidate for these, interacts with NKX2.5.

Talk to Fanny about this? need not, he will continue working on it.

Dominique Bonneau, C Cipierre, D Guichet

Baby born in June, 5th child, lymphangioma kystique, paracervical L – agenesis renal L, hypoplasie pulmonaire, hemithoras – missing ribs, but pelvis is ok. The clavicule seems to be there, not the omoplate.

Agathe Paubel, Tours

  • Agenesis of rachis dorso-lombo-sacrum
  • Could see some C1-C7 in echo, nothing in lombosacral, a few random ribs. Limbs: arthrogrypose and campylodactyly. Heart leaning to right, umbilical artery 1 only on L. No formation of uterus in female fetus.
  • Single kidney median with both ureters on right. Double, symmetric thymus. Just a few hemivertebrae, 6-7 irregular ribs. Iliac crests present, also omoplates.

15 cases described in Bohning AJMG 1999 87:99-114. Interrupted spinal cord in MRI image in this paper. Left isomerism for lungs described. Clefts and microtia described, as well as cardiac PBs – VIC, pulm arteries.

  • Association with maternal diabetes?
  • Retinoic acid anomaly as described by Nicolas? But how does this translate into not so different

What about PITX2 (not c)? This is rather like very little of the paraxial and intermediate mesoderm survived – or couldn’t stay apart once specified. Need SHH to keep the domains apart? What about a RARE in SHH?

  • If too high FGF8 in PSM get squished-up somites (Pourquie group). Irregular in Raldh2-/- background.
  • Why is the thymus separate? That’s an endodermal derivative, usually median. So what’s apart comes together (or is gone) and what is usually median stays separate (or is gone like sternum).

Patrick Edery

  • Idiopathic scoliosis
  • It is a quantitative trait with more than 10 degrees incurvation. For Smith Magenis get 50% secondary scoliosis, as well as in CHARGE syndrome.
  • Melatonin! All chickens w/o pineal gland become scoliotic Machida et al Spine 1993. Not clear how to check in patients. Signaling pb? Moreau et al Spine 2004: in vitro study b/c diminishes cAMP. Both melatonin and forskolin bind MT1 and MT2 then adenylate cyclase inhibited and cAMP accumulates physiologically (eh?).
  • Meanwhile, Patrick worked with Francoise Clerget-Darpoux. 40% familial cases. 90% concordance in twins.Girls 4x more than boys.
  • Linkage studies, polymorphisms in CHD7 (Gao 2007), SNTG1, MATH1. Plenty of other loci. Disruption of CHD2 by balanced translocation in mental retardation + scoliosis cf Kukami 2008. But no other major gene yet.
  • 45 multiplex families – 6 big – 388 individuals, whole genome genotyping for the 6 families. Quantitative (>15º incurvation)… passed on MERLIN. One big familyLOD 3.31 for family 2, 3.47 in another region, and in families 4-6 a few candidate loci up to LOD 2.1. Nothing in family 1. Sequenced a good candidate, found nothing.

Marie Gonzales

  • Synspondyly
  • 1st case 1991 : Hernie diaphragmatique, vertebrae – ok vertebrae, fusion of spinal processus dorsal/cervical.
  • 2nd cas Koyl…. 1992: CIV haute, coupoles diaphragm. Hautes, head in the shoulders, exact same spine. Space, then fusion, then space (with vertebrae) then more fusions.
  • 3rd and 4th cases from Martine (she has a 5th without the filamin B mutation or noggin) – want to check Filamin B – prenatal form.. Steve Robertson in NZ does the sequencing.


  • AR family. Meningocoele lumbosacral, cystic kidneys, hypoplastic nails, short trunk, short neck, malpositioned feet, short, “open zipper” at end of spine, no sacrum. Sister had vertebral bodies at level of spina bifida. Earlier death no spina bifida but the same kidneys and vertebrae. Abnormal pelvis area, high pelvis.
  • Martine has other similar cases (one from Bohring) with truncated 3e phalange, loss of vertebral bodies (all the rest ok). Cf article published in 2005. Also exclusion of PAX1/MEOX1. Non-ossification of the vertebrae (they’re there, the vertebral bodies).
  • Nephroblastomatosis

Sophie Julia from Toulouse

  • Akinesie foetale/arthrogryposis in family (earlier sister); this girl has facial dysmorphia, hydrocephaly, CIV+CIA, retard psychomoteur, hypotonie, high myopia, severe scoliosis, cutaneous hyperlaxity.
  • Demineralisation, fractures: osteogenesis imperfecta? Treated as such in any case – started treatment on biphosphonate. (not necessarily ideal treatment…)
  • Bruck syndrome? Combination of the two of arthrogryposis and osteogenesis imperfecta but more Ehlers-Danlos-like. The Bruck children have contractures at birth but are not dysmorphic cf Martine. Also not a “real” OI – demineralization, suggest to pass on CGH. Lysyl hydrolysase 2 gene (PLOD1/PLOD2) – possible ED type VI. There is also a PLOD3. Maturation of collagen I.


  • Sophie also evoked a case of lung and limb agenesis. The first case she encountered and left in Marseille; it was total. The second fetus is at Toulouse, more phocomelic – hand attached. Similar to our Yac- case. Wnt3 mutations published have no limbs but there is no problem in the lung. Want to look at enhancer/promoter regions controlling FGF10 expression in the limb and lung.

Marion (R. Debre)

“Prune belly” – show half: agenesis of hemiabdominal muscles on left with deformation, otherwise same. And hemivertebrae T8-11 and agenesis of the left ribs 9-12. Also absence of the corresponding nerves. Ok brain and kidneys.

  • Another case: severe scoliosis at 20sa and prune belly. Born otherwise ok but again loss of the abdominal musculature. Vertebrae not in hemi but 90º scoliosis. Missing still T9-12 lateral arch. Diaphragmatic hernia but the muscle is missing as well as an opening with liver up into chest cavity. Operated and placed a “plaque de Vicryl. Sort of v-shaped vertebrae “fentes”. The cause of “prune belly” would not be a megabladder.

Brigitte Gilbert-Dussardier

  • Bilateral microphthalmia with arthrogryposis distal feet/hands and osteotomy bilateral of the femurs through the elbows/knees ok. Hands – severe camptodactyly R and esp in 5th finger, extensor thumb L, dysmorphic slight asymmetry with high palate and small chin, nystagmus/cataract.

Scoliosis at 8y. Normal intelligence. Muscle biopsies ok.

  • Cyst above the vermis, no other pb. CCA (congenital contractural arachnodactyly) syndrome (no ear says Didier though she doesn’t have an earlobe; no eye pbs described) or Beals? Wants to look at fibrillin 2? Or “Gordon”? Dominique interested by that idea. Nicolas suggested an “acro…” I don’t know what.

Everyone is thinking that she doesn’t have a phenotype like Beals (everyone except me because I didn't know what it was before today).

  • Neomutation dominante… but of what? Martine wants to look at Walker-Warburg syndrome.


  • With Marie-Josée Perez described a polymalformative syndrome with hydrocephaly. X-linked looking at L1CAM. The fetus has spinal anomalies as well as renal and anorectal malformation with sacral agenesis. Fusions of C3+C4, C5+C6; hemivertebrae in thoracic and lumbar areas. Earlier boy fetus not hydrocephalus. Wonders if unrelated. No microremaniments. Possible mother diabetic?... not much more discussion.

Véronique David / Sylvie Odent

  • Holoprosencephaly
  • 1/250 abortions, but 1/16000 live births.
  • Not confirmation of FAST1, TDGF1, PATCHED, GLI2 so much – Max Muenke, in addition to the more frequent mutations in SHH, ZIC2, SIX3, TGIF (but the four of these only explain <30% of the current cases);
  • Rearrangements via QMPSF, MMPA see that the genes are often subtelomeric. 182 patients found 8 rearrangements in these regions. (now up to HPE12).
  • Now CGH array with Agilent 44K now 244K.
  • Lots of rearrangements, certain are pretty small: 24 deletions, 11 duplications, 5 del/dupl. (30% of the cases!) from 1 gene to 30Mb (was missed in karyotype! But Didier’s group laughs because they once missed a 18Mb deletion also and caught it in CGH array).

anosterol synthase?

  • Prioritize genes and find redundancies to look for candidate genes. Eg: 20p C20orf133 (“MacroD2” and FLRT3 which is *inside* the other gene) in a CNV region but this C20orf133 area deleted also in a Kabuki patient – Damien Sanlaville and Stanislas and David Genevieve are in the middle of this 2007 paper and audience is not sure that it really looks like a Kabuki? Found other C20ORF133 deletion patients in the same part of the gene; turns out it is a CNV region and that can not be related to the pathology in either situation);
  • PATCHED3 on 10p. Not much about its expression. Very conserved and also with a pseudogene. Muenke has found many PTCH1 except in the end only one really – a little in doubt?
  • 5p: TPPP is deleted or duplicated in 4 patients.
  • Endeavor program by Yves Moreau in Leuven. to help attribute a priority score.

Sequencing but… Expression profile in chicken embryo/mouse and maybe will go to RNAi in mouse or Xenopus. (Claude Bendavid MCU-PH) Valerie Dupé – inhib Shh by cyclopamine concentrations fgoing from 1-2.5g at stages 5-9; vulnerability particularly at stages 6-7.

  • Patient 342 has a del 20p of 5.6MB with FOXA2 and NKX2.2 deletion, looking at which is affected by cyclopamine treatment (both are eliminated in the chicken embryo). I like the former gene but should be more dramatic than that? then again, Shh isn't...
  • Still, few redundant regions, and lots of genes.
  • Sylvie approached me earlier to talk about cases of HPE with laterality defects – if it isn’t ZIC2, what else could it be?

Cecile Cipierre (Angers)

  • Hypocalcemia. Early apnea and erythmodermia, slight dysmorphy but the ears are distinctive, small; desquamation of feet; small canal arterial, permeable foramen oval, pbs swallowing. Also hypocalcemia in grandmother and mother – hypoparathryoidism. Boy doesn’t have any thymus, this was a del 22q11 that the mother had. Died at 7 mo. Severe immunodeficiency. Also arhinencephaly.
  • Another published case has an erythrodermia and peeling with DiGeorge.

2nd case: February 2008. Calcified placenta, congenital torticolli, general erythema from face to whole body but desquamation of skin from birth. At 3 mo. Hospitalized. Loss of dark hair, keep light and sparse. Stayed small, not thriving. Axial hypotonia, diarrhea – enteropathy auto-immune? * Problems in digestive epithelium. Hypoalbumineria and immune defect as well as anemia. (Myelogram is normal but hyperleucocytosis). Skin biopsy – not ichthyosis but sort of psoriasis. Hairs have fractures… “nodosites”

  • This guy has thymus, dysplasia in metaphyses (splayed) but not incurvated.
  • Evokes Netherton not so much..? More Omenn syndrome – alopecia, but no bone pb described. Most probable Cartilage-hair hypoplasia although erythrodermia has not yet been described, but the diarrhea and bone pbs yes. Skin pb

Caroline Rooryck Thambo (Bordeaux)

  • Oculocutaneous albinism

(4 types, most common is the OCA2)

  • Dysfunction of TYR, TYRP1/2, MATP, TRP1/2….enzymes metabolizing tyrosine to dopaquinone to eumelanins or phaeomelanins. (tyrosinase is way up in the list for both kinds, whereas the TRP1/2 are in the eumelanin path.
  • The melanocytes is quite spider-like dendritic.
  • Secretion of mélanosomes is also regulated by maturation enzymes that can be mutated in OCA variants (but the mélanosomes get trashed early on and not exported to kératinocytes). Agouti protein is co-binding the alpha-MSH receptor MC1R to block its binding by alpha-MSH.

OCA2 = “P” gene. MATP or SLC45A2 – membrane associated transporter protein. Relatively frequent. Tyrosinase (TYR) is OCA1.

  • QMPCR shows that there are a certain number of deletions in OCA2 (less severe than OCA1).
  • Can have OCULAR albinism only affecting eye with mutations in TYR – a variant + a severe allele. Cf Hutton et al 2008. Showed little girl not at all depigmented. Nystagmus but even the iris is pigmented.
  • Described two OCA2 families – different both from New Caledonia Wallis/Melanesia; htz A355E G775D both de novo, and associated with “axial” mesodermic dysplasia. Dysostosis spondylocostal is associated in the family but that is fortuitous because of consanguinity.
  • Possibility of “triallelism” in some cases eg two TYRP1 and 1 TYR mutation from father and mother; also in OCA2 and TYRP1.


A cytogeneticist from Rennes, works with Sylvie and Veronique:

  • 1st case - C... has dysmorphie – long hands.feed, anteposition anale, hypoplasie CC, scoliose by 4y, RM, retard de croissance, microcephaly, insuffisance renale. Lots of chromosomal problems: on chr 1, 2, 9 with derivatives all over the place as well as a transloc between chr 11 and 14. CGH array Agilent show deletion in 1q23.3-q23.2 3Mb deletion more or less.
  • 2nd case: PND at 32sa – small femurs, cyst in arachnoid posterior fossa, reciprocal balanced translocation chr 2-10 (2q?24 with 10p14) or 10p15. Wondering if little abnormality also on chr 5, a bit of 2q22-23 on der 5 and other bit on 10 as well as 2q33 deletion.
  • IMG 37sa with dysmorphie faciale micrognath hypertel, cou court/large, coarct aorte,…
  • De novo complicated remaniments like this are often predisposed from the paternal contribution. When they are apparently balanced can be familial but the abnormal phenotypes can be assoc RM and tend to be de novo.
  • National organization of research project to collect all apparently balanced translocations to get onto CGH arrays such as Agilent – Patrick Edery with Damien says not ready for prenatal – how validate, problem with delay for interpretation of data; ethical problems vs certain deletions and their interpretation? He thinks it is premature. There is a PHRC exactly for this that was proposed that Didier Lacombe saw perhaps criticism to do in prenatal not give results, needs to go through Agence de Biomedecine and perhaps be done at a national level. Veronique brings up the time issue also.

Brigitte Benzacken GHU Nord cytogenetics and Catherine Vincent-Delorme

  • Paternal chromosomal anomalies – genetic counseling
  • A... had 18p+ as well as 46, XY. Parents normal. Now 28yo. Slightly small, but IQ 67. Somewhat socially adapted. The girlfriend gets pregnant. A's’ parents asks for consultation. Fetus 14sa in March. Checked with FISH. In fact a deletion of telomeric area 18p11.32 and duplication of subtelomeric region in p11.31 with inversion.
  • The baby underway is normal (phew) and wonder if need to look further in parents or not as to other members of the family. If had found a problem, would have referred to echo or MRI.

Magali (Barthe?) chef from Angers

  • Presents metabolism problems. Started after went off maternal milk. Constant diarrhea, purpura (mechanical) develops at 7 mo. High fever in Morocco and CD8 lymphopenia. Transfer to Necker for bone marrow graft, no hepatomegaly. RM, dystonia. MRI: Cortical atrophy, patchy perhaps vascular problems, heart/EEG normal.
  • Metabolic problems – for redox, permanent hyperlactacidemia. B oxidation on lymphocytes is normal, but partial deficit of complex 4 mito on the lymphocytes. Homozygous deletion of exon 4 of the gene ETHE1 (chr 19q13 gene). Ethylmalonic encephalopathy : this gene maybe helps make mitochondrial matrix but not very clear.
  • 12 cases with the psychomotor retardation. Vascular problems with the tortuous vessels and pulmonary hemorrhaging sometimes (as well as the purpura), irregular cerebral arteries and dilatation of the perforating arteries.
  • MRI looks like Leigh syndrome, glutartic acidopathy. What is getting to be toxic and can something be done about it? Methionine-poor diet possibly or poor in fats. Carnitine aside..?

Cyril Goizet – Bordeaux, INSERM U679

  • Hereditary Spastic Paraplegias
  • Strumpell-Lorrain (also work with Al. Brice)
  • 38 loci and so far 16 genes ID’d. “Pure” and complex forms. All heredities. Onset at any age. Atteinte pyramidale. Hyper-reflexes or real spasticity, or progressive muscular weakness and stiffening of legs.
  • The spasticity can be other than HSP of course.
  • Can also have urinary problems. Pure forms have normal MRI, normal life span. Complex forms can have same but also cerebellar ataxia, mental retardation, distal amyotrophy, deafness, cataract/retinitis pigmentia or macular degeneration, shorter life span.
  • SPG3A early onset, SPG4 is 40% of autosomal dominant forms and 10-15% of the pure sporadic forms as well. The other forms are much less frequent. 3rd most frequent form is at 6.5% SPG31.
  • The SPG4 gene is big and mutations or intragenic deletions a little all over the place. Implicated in axonal transport.
  • Recessive forms – 4 genes in complex forms = paraplegin, etc. 1 gene so far ID’d in pure forms (previous SPG5). Reviewed in Stevanin Curr Neuro Neurosci Report 2008.
  • SPG31

Working on SPG31 = REEP1 found in the mitochondria, with 19 mutations most of which are truncating, two affect miRNA binding sites. Zuchner Am J Hum Genet 2006. Leads to both pure and complex forms. Onset at around 20 years, handicap mild to moderate; one in wheelchair after a brush with Lyme syndrome. Two patients started to show up because of Silver phenotype in hands before onset in the legs.

  • Kinesin motor region of SPG10 since it’s 50 exons long. Found hotspot in 3/8 families with mutations. Again, mild-to-moderate handicap and adult onset. But all had a complex form. One other member of family has peripheral neuropathy or other things.
  • SPG5

– AR form. Mutations in CYP7B1 (Am J Hum Genet 2008). Codes for a cytochrome p450 in liver and brain. Cholesterol metabolism (CYP7A1 is in classic pathway but the 27A1 and 7B1 goe into the “acidic” pathway as well as metabolism of DHEA. Younger onset, more moderate to severe. One family also has chronic hepatitis and member died from cirrhosis and liver failure, one peripheral neuropathy, white matter problems in MRI but how assoc with disease?

  • SPG11

Predominant form, cloned A Brice published recently. Spatacsin. 40 odd exons. Expressed a little everywhere but also in pineal gland.

  • HSP with thin corpus callosum: 6 loci

(SPG7 one case, SPG11, SPG15, 21, 32…) Common in recessive forms, recently described; early onset, rapid paraplegia and severe handicap, peripheral neuropathy, white matter hyperintensitites. Mental retardation or dementia.

  • SPG15

Assoc with RP, same localization as SPG11.