ozi

Ọ bụ ezie na ọ dị ụkọ, ọnụ ọgụgụ zuru ezu nke nchekwa lysosomal bụ ihe dịka 1 n'ime 5,000 ọmụmụ ọ bụla. Na mgbakwunye, n'ime ihe fọrọ nke nta ka ọ bụrụ 70 a ma ama lysosomal nchekwa nchekwa, 70% na-emetụta usoro nhụjuanya nke etiti. Ọrịa ndị a otu mkpụrụ ndụ ihe nketa na-akpata dysfunction lysosomal, na-ebute nsogbu nke metabolic, dysregulation nke protein nke rapamycin (mTOR, nke na-egbochikarị mbufụt), autophagy na-adịghị mma, na ọnwụ mkpụrụ ndụ akwara. Ọtụtụ usoro ọgwụgwọ na-ezubere usoro pathologic dị n'okpuru nke ọrịa nchekwa lysosomal ka akwadoro ma ọ bụ na-etolite, gụnyere ọgwụgwọ nnọchi enzyme, ọgwụgwọ mbelata mkpụrụ osisi, ọgwụgwọ chaperone molecular, ọgwụgwọ mkpụrụ ndụ ihe nketa, ndezi mkpụrụ ndụ ihe nketa, na ọgwụgwọ neuroprotective.

Niemann-pick ọrịa ụdị C bụ lysosomal nchekwa cellular kọlestrọl mbugharị nsogbu nke bialelic mutations na ma NPC1 (95%) ma ọ bụ NPC2 (5%). Ihe mgbaàmà nke ụdị C nke ọrịa Niemann-Pick na-agụnye ngwa ngwa, na-egbu egbu akwara na nwata, ebe ndị na-eto eto, ndị na-eto eto na ndị okenye na-amalite na-agụnye splenomegaly, supranuclear gaze paralysis na cerebellar ataxia, dysarticulationia, na dementia na-aga n'ihu.

N'ime mbipụta akwụkwọ akụkọ a, Bremova-Ertl et al na-akọ nsonaazụ nke nyocha abụọ nke kpuru ìsì, ebe a na-achịkwa placebo, ikpe crossover. Ọnwụnwa ahụ na-eji onye na-ahụ maka neuroprotective nwere ike, amino acid analogue N-acetyl-L-leucine (NALL), iji na-agwọ ụdị ọrịa Niemann-Pick C. Ha na-ewe ndị na-eto eto 60 Symptomatic na ndị ọrịa okenye na nsonaazụ gosipụtara ọganihu dị ịrịba ama na ngụkọta akara (isi njedebe) nke Ataxia Assessment and Rating Scale.

Nnwale ụlọ ọgwụ nke N-acetyl-DL-leucine (Tanganil), agbụrụ agbụrụ nke NALL na n-acetyl-D-leucine, yiri ka ọ bụ ahụmahụ na-akpali akpali: usoro ihe omume emebeghị nke ọma. A kwadoro N-acetyl-dl-leucine maka ọgwụgwọ nke nnukwu vertigo kemgbe 1950s; Ụdị anụmanụ na-atụ aro na ọgwụ na-arụ ọrụ site n'ịhazigharị overpolarization na depolarization nke medial vestibular neurons. N'ikpeazụ, Strup et al. kọrọ nsonaazụ nke ọmụmụ nwa oge nke ha hụrụ mmụba nke mgbaàmà na ndị ọrịa 13 nwere degenerative cerebellar ataxia nke etiologies dị iche iche, nchọpụta nke mere ka mmasị na-eleba anya na ọgwụ ahụ ọzọ.

Usoro nke n-acetyl-DL-leucine na-eme ka ọrụ akwara dịkwuo mma ka amabeghị, mana nchọpụta dị na ụdị òké abụọ, otu n'ime ụdị ọrịa Niemann-Pick C na nke ọzọ nke ọrịa nchekwa nchekwa GM2 ganglioside Variant O (ọrịa Sandhoff), ọrịa lysosomal neurodegenerative ọzọ, emeela ka uche gaa na NALL. Kpọmkwem, nlanarị nke Npc1-/- ụmụ oke ejiri n-acetyl-DL-leucine ma ọ bụ NALL (L-enantiomers) kwalitere, ebe nlanarị nke ụmụ oke ejiri n-acetyl-D-leucine (D-enantiomers) emebeghị, na-atụ aro na NALL bụ ụdị ọrụ ọgwụ. N'ime ọmụmụ ihe yiri nke ahụ nke GM2 ganglioside nchekwa variant O (Hexb-/-), n-acetyl-DL-leucine rụpụtara ogologo ndụ dị mma ma dị ịrịba ama nke ụmụ oke.

Iji nyochaa usoro omume nke n-acetyl-DL-leucine, ndị nchọpụta nyochara ụzọ metabolic nke leucine site na ịlele metabolites na anụ ahụ cerebellar nke anụmanụ mutant. Na ụdịdị O dị iche iche nke nsogbu nchekwa nchekwa GM2 ganglioside, n-acetyl-DL-leucine na-emezi glucose na glutamate metabolism, na-abawanye autophagy, ma na-abawanye ọkwa nke superoxide dismutase (onye na-ekpochapụ oxygen na-arụ ọrụ). N'ụdị C nke ọrịa Niemann-Pick, a hụrụ mgbanwe na glucose na metabolism antioxidant na mmụgharị na metabolism ike mitochondrial. Ọ bụ ezie na L-leucine bụ onye na-arụ ọrụ mTOR siri ike, ọ dịghị mgbanwe ọ bụla na ọkwa ma ọ bụ phosphorylation nke mTOR mgbe a gwọchara ya na n-acetyl-DL-leucine ma ọ bụ enantiomers na ụdị òké ọ bụla.

A hụla mmetụta neuroprotective nke NALL n'ụdị òké nke ihe mgbochi cortical kpatara mmerụ ahụ ụbụrụ. Mmetụta ndị a na-agụnye ibelata akara nrịbama neuroinflammatory, ibelata ọnwụ cell cortical, na melite mgbanwe autophagy. Mgbe ọgwụgwọ NALL gasịrị, moto na ọrụ ọgụgụ isi nke ụmụ oke merụrụ ahụ na-eweghachite ma belata ọnya ahụ.

Nzaghachi mkpali nke usoro nhụjuanya nke etiti bụ ihe ama ama nke ọtụtụ nsogbu nchekwa lysosomal neurodegenerative. Ọ bụrụ na enwere ike ibelata neuroinflammation na ọgwụgwọ NALL, ihe mgbaàmà ụlọ ọgwụ nke ọtụtụ, ma ọ bụrụ na ọ bụghị ihe niile, enwere ike imeziwanye nsogbu nchekwa lysosomal neurodegenerative. Dị ka ọmụmụ ihe a na-egosi, NALL na-atụkwa anya inwe mmekọrịta na usoro ọgwụgwọ ndị ọzọ maka ọrịa nchekwa lysosomal.

Ọtụtụ nsogbu nchekwa lysosomal na-ejikọta ya na cerebellar ataxia. Dị ka otu ọmụmụ mba ụwa metụtara ụmụaka na ndị okenye nwere nsogbu nchekwa nchekwa GM2 ganglioside (ọrịa Tay-Sachs na ọrịa Sandhoff), ataxia belatara na ezigbo nhazi moto na-emeziwanye mgbe ọgwụgwọ NALL gasịrị. Otú ọ dị, nnukwu, multicenter, okpukpu abụọ kpuru ìsì, randomized, placebo-controlled trial gosiri na n-acetyl-DL-leucine adịghị arụ ọrụ nke ọma na ndị ọrịa nwere ngwakọta (eketa, ndị na-eketaghị, na ndị na-enweghị nkọwa) cerebellar ataxia. Nchọpụta a na-egosi na enwere ike ịhụ nrụpụta ọrụ naanị n'ime ule metụtara ndị ọrịa nwere ataxia cerebellar ketara eketa na usoro ejikọtara ya nyocha. Na mgbakwunye, n'ihi na NALL na-ebelata neuroinflammation, nke nwere ike ibute mmerụ ahụ ụbụrụ, enwere ike ịtụle ule nke NALL maka ọgwụgwọ nke mmerụ ahụ ụbụrụ.